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The American Journal of Pathology, Vol. -, No. -, - 2015
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ASIP COTRAN EARLY CAREER INVESTIGATOR AWARD LECTURE Multiple Mechanisms of Unfolded Protein ResponseeInduced Cell Death Q27
Nobuhiko Hiramatsu, Wei-Chieh Chiang, Timothy D. Kurt, Christina J. Sigurdson, and Jonathan H. Lin From the Department of Pathology, University of California-San Diego, La Jolla, California Accepted for publication March 26, 2015.
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Address correspondence to Jonathan H. Lin, Department of Pathology, University of California-San Diego, 9500 Glitman Dr, La Jolla, CA 92093-0612. E-mail: jlin@ ucsd.edu.
Eukaryotic cells fold and assemble membrane and secreted proteins in the endoplasmic reticulum (ER), before delivery to other cellular compartments or the extracellular environment. Correctly folded proteins are released from the ER, and poorly folded proteins are retained until they achieve stable conformations; irreparably misfolded proteins are targeted for degradation. Diverse pathological insults, such as amino acid mutations, hypoxia, or infection, can overwhelm ER protein quality control, leading to misfolded protein buildup, causing ER stress. To cope with ER stress, eukaryotic cells activate the unfolded protein response (UPR) by increasing levels of ER protein-folding enzymes and chaperones, enhancing the degradation of misfolded proteins, and reducing protein translation. In mammalian cells, three ER transmembrane proteins, inositol-requiring enzyme-1 (IRE1; official name ERN1), PKR-like ER kinase (PERK; official name EIF2AK3), and activating transcription factor-6, control the UPR. The UPR signaling triggers a set of prodeath programs when the cells fail to successfully adapt to ER stress or restore homeostasis. ER stress and UPR signaling are implicated in the pathogenesis of diverse diseases, including neurodegeneration, cancer, diabetes, and inflammation. This review discusses the current understanding in both adaptive and apoptotic responses as well as the molecular mechanisms instigating apoptosis via IRE1 and PERK signaling. We also examine how IRE1 and PERK signaling may be differentially used during neurodegeneration arising in retinitis pigmentosa and prion infection. (Am J Pathol 2015, -: 1e9; http://dx.doi.org/10.1016/j.ajpath.2015.03.009)
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The endoplasmic reticulum (ER) is an essential organelle responsible for folding of secreted and membrane proteins and lipid and sterol biosynthesis, and it is a major site of free calcium storage within the cell. Cells have evolved a unique homeostatic mechanism, termed the unfolded protein response (UPR), to ensure that the ER can adapt to changing environmental and physiological demands of its functions. In mammalian cells, the UPR is controlled by the ER resident transmembrane proteins, inositol-requiring enzyme-1 (IRE1; official name ERN1), PKR-like ER kinase (PERK; official name EIF2AK3), and activating transcription factor-6 (ATF6). IRE1 is a transmembrane protein that controls a UPR signal transduction pathway conserved from yeast to mammals 1 ½F1 (Figure 1). IRE1 bears a luminal domain coupled across the ER membrane to cytosolic kinase and endoribonuclease (RNase)
domains.1 In response to ER stress, IRE1 undergoes oligomeric assembly, transautophosphorylation by its kinase domain, and activation of its distal RNase activity.2,3 In metazoans, the RNase activity of activated IRE1 and the RtcB tRNA ligase splice out a small intron from the X-box binding protein-1 (Xbp1) mRNA to produce XBP1s transcription factor.4e8 Supported by NIH grants R01EY020846, R01NS069566, R01NS076896, and R01NS088485 and VA grant BX002284. Disclosures: None declared. The American Society for Investigative Pathology Cotran Early Career Investigator Award recognizes early career investigators with demonstrated excellence as an investigator with recently established or emerging independence and with a research focus leading to an improved understanding of the conceptual basis of disease. Jonathan H. Lin, recipient of the ASIP 2013 Cotran Early Career Investigator Award, delivered a lecture entitled Endoplasmic Reticulum Stress in Disease Pathogenesis on April 22, 2013, at the annual meeting of the American Society for Investigative Pathology in Boston, MA.
Copyright ª 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajpath.2015.03.009
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Endoplasmic reticulum (ER) stress activates inositol-requiring enzyme 1 (IRE1), PKR-like ER kinase (PERK), and activating transcription factor-6 (ATF6) intracellular signal transduction pathways of the unfolded protein response (UPR). In normal condition, the UPR transducers, IRE1, PERK, and ATF6, associate with BiP to prevent UPR. On accumulation of misfolded proteins in the ER lumen, BiP dissociates to activate UPR transducers. IRE1 bears a luminal domain coupled across the ER membrane to cytosolic kinase (K) and endoribonuclease (RNase) domains (R). In response to ER stress, IRE1 undergoes oligomeric assembly, transautophosphorylation by its kinase domain, activating its distal RNase activity. Activated IRE1 splices out small intron from the X-box binding protein-1 (Xbp1) mRNA to generate active transcription factor XBP1s. The PERK protein bears luminal domain coupled across the ER membrane to K. In response to ER stress, PERK dimerizes and subsequently activates its cytosolic kinase domain. PERK’s kinase recognizes and phosphorylates eukaryotic translation initiation factor 2 subunit alpha (eIF2a), leading to attenuation of global protein translation. ATF6 bears an ER-tethered transcription factor. In response to ER stress, ATF6 migrates from the ER to the Golgi apparatus, where site 1 and 2 proteases (S1P and S2P, respectively) cleave its luminal and transmembrane domains, and release the cytosolic portion of ATF6 containing the bZIP transcriptional activator domain. Cleaved ATF6 fragment translocates to the nucleus to serve as a transcription factor.
The transcriptional targets of XBP1 are highly enriched for ER-associated protein degradation (ERAD) factors, ER chaperones, and enzymes required for lipid biosynthesis and protein glycosylation across diverse mammalian cell types.9e14 Up-regulation of these molecules by IRE1-toXBP1s induction therefore enhances the ER’s capacity to better fold new proteins as well as target irreparably damaged proteins for retrotranslocation out of the ER for degradation by proteasomes in the cytosol (Figure 1). The ER transmembrane protein PERK regulates another UPR signaling pathway in metazoans15 (Figure 1). On ER stress, PERK oligomerizes and activates its cytosolic kinase domain.15 PERK’s kinase phosphorylates eukaryotic translation initiation factor 2 subunit alpha (eIF2a) on Ser51, inhibiting the guanine nucleotide exchange factor eIF2B, which converts inactive GDP-bound eIF2 to its active GTP form.15,16 Active eIF2 complex is needed to form the GTP-tRNAMet ternary complex required for translation initiation. Therefore, eIF2a phosphorylation leads to translation inhibition that helps alleviate ER stress by reducing the load of new polypeptides that require assembly and folding in the ER compartment.17 ATF6 bears an ER-tethered bZip transcription factor that regulates a third UPR signal transduction pathway18 (Figure 1). In response to ER stress, ATF6 migrates from the ER to the Golgi apparatus, where site 1 protease and site 2 protease cleave its luminal and transmembrane domains to release the cytosolic portion of ATF6.18,19 The cytosolic
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portion of ATF6 contains the bZIP transcriptional activator domain, and after cleavage, this ATF6 fragment migrates to the nucleus to transcriptionally up-regulate ER chaperones and ERAD components, thereby enhancing ER proteinfolding capacity and efficiency of ERAD.10,12,18,20 Interestingly, ATF6 also transcriptionally up-regulates Xbp1, thereby facilitating IRE1 signal transduction by increasing levels of IRE1’s RNase substrate, Xbp1 mRNA.21 Put together, these initial transcriptional and translational effects of IRE1, PERK, and ATF6 signaling help cells adapt to ER stress by enhancing the fidelity of protein folding, increasing the degradation of damaged/misfolded proteins, and suppressing new protein synthesis. However, if these actions fail to restore ER homeostasis and ER stress persists, UPR signaling consequently triggers maladaptive proapoptotic programs, many of which are specifically activated through the IRE1 and PERK pathways.
IRE1 Signaling Independent of XBP1: RIDD, c-Jun N-Terminal Kinase, and BCL2 Seminal mechanistic studies from the laboratory of Walter and colleagues have revealed that IRE1 undergoes dynamic conformational and functional changes as a function of the duration of ER stress. In response to acute ER stress, IRE1 quickly forms oligomeric clusters in the ER plane, but IRE1
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Consequences of acute and chronic inositol-requiring enzyme 1 (IRE1) activation. In response to acute endoplasmic reticulum (ER) stress, IRE1 undergoes oligomeric assembly, undergoes transautophosphorylation by its kinase domain, and activates its distal RNase activity. Activated IRE1’s RNase splices out a small intron from the X-box binding protein-1 (Xbp1) mRNA to produce the active transcription factor XBP1s. IRE1-to-XBP1s induction enhances the ER’s capacity by up-regulation of gene sets involved in ER-associated protein degradation (ERAD), ER chaperones, lipid biosynthesis, and protein glycosylation. In the chronic phase of IRE1 activation, IRE1’s RNase domain cleaves ER-targeted mRNAs in a phenomenon termed regulated IRE1-dependent mRNA decay (RIDD). Most RIDD-targeted mRNAs are disposed. In contrast, IRE1-dependent cleavage of the 30 untranslated region of BiP mRNA in Schizosaccharomyces pombe stabilizes BiP mRNA, thereby increasing BiP protein levels to cope with ER stress. There is likely a regulated IRE1-dependent mRNA stabilization (RIDS) rather than RIDD, which may be a new mode by which IRE1’s RNase positively regulates mRNAs. The TRAF2 adaptor protein binds to IRE1 and the MAPKKK ASK1 to activate downstream molecules such as c-Jun N-terminal kinase (JNK), p38, and extracellular signaleregulated kinase (ERK). However, it is unclear which phase of IRE1 activity can interact with TRAF2-ASK1. Angptl, ---; Ces, ---; Cyp, ---; DR5, death receptor 5.
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subsequently dissociates if ER stress persists (Figure 2).22,23 Interestingly, Xbp1 mRNA splicing only occurs during the acute phase.23e25 During the chronic phase of ER stress, IRE1’s RNase substrate specificity is altered to cleave primarily ER-targeted mRNAs in a process termed regulated IRE1-dependent mRNA decay (RIDD)26e28 (Figure 2). In contrast to Xbp1 mRNA, RIDD targets are not ligated after IRE1 cleavage, and most mRNA fragments cleaved through RIDD are degraded. RIDD’s physiological significance varies widely and can confer protective or proapoptotic effects, depending on the cellular function of the mRNA being targeted. RIDD-mediated cleavage of death receptor 5 (DR5) mRNA enhances cell survival during ER stress by reducing production of proapoptotic DR5 protein.29 RIDD-mediated cleavage of cytochrome P450 enzyme mRNAs in liver confers resistance to liver damage after acetaminophen overdose by preventing P450-mediated generation of hepatotoxic byproducts.30 The mRNA fragments produced by RIDD cleavage can trigger inflammation by engaging with the cytosolic RIG1 RNA virus innate immunity sensor.31 RIDD-mediated loss of lipid metabolism mRNAs can alter plasma lipid levels in mice.32 Ire1 mRNA itself is a RIDD substrate, and RIDD may act as an autoregulatory brake on IRE1 signaling by down-regulating Ire1 mRNA levels.33 miRNA precursors have also been identified as RIDD substrates in vitro.34 Disruption of miRNA maturation by RIDD cleavage may further affect multiple biological processes by modulating miRNA-mRNA interactions throughout the cell.
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Recently, IRE1’s RNase was found to cleave the 30 untranslated region of BiP mRNA in Schizosaccharomyces pombe, but this truncation surprisingly stabilized, rather than promoted, the decay of the remaining BiP mRNA, thereby increasing BiP protein levels during ER stress.35 Regulated IRE1-dependent mRNA stabilization, rather than RIDD, may be a new mode by which IRE1’s RNase positively regulates mRNAs (Figure 2). Recent biochemical studies have suggested that IRE1 uses RIDD at intense ER stress levels, whereas Xbp1 mRNA splicing is initiated at much lower levels of ER stress25 (Figure 2). IRE1’s decision to trigger RIDD, regulated IRE1-dependent mRNA stabilization, or Xbp-1 mRNA splicing may be dependent on the intensity of the stress and the ability of various cell types to respond to that stress. The IRE1 oligomeric clusters formed by ER stress also act as molecular scaffolds to recruit other proteins and nucleate the formation of stress signal transduction sites at the ER lipid bilayer22,23 (Figure 2). For example, TRAF2 adaptor protein binds to IRE1 as well as the ASK1 MAPKKK to activate cytosolic signaling kinases, such as C-Jun N-terminal kinase, p38, and extracellular signaleregulated kinase during ER stress36,37 (Figure 2). IRE1 also interacts with the RACK1 adaptor protein to recruit phosphatases to the ER membrane during ER stress.38 IRE1 forms protein-protein interactions with BCL2 family proteins, such as BAX and BAK, and the BI-1 BCL2 regulatory protein.39,40 IRE1 also binds cytoskeletal nonmuscle myosin II during ER stress.41 These
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373 Normal Acute Phase Chronic Phase 374 375 376 377 378 P 379 P K K PP K K PP K P P 380 P P P P 381 P 382 P eIF2α eIF2α Translation 383 eIF2α Attenuation 384 40S 385 60S GADD34 ATF4 Degradation IAPs 386 Casp 387 Translation Inactive Attenuation 388 389 CHOP Redox Golgi 390 Genes 391 DR5 392 Casp 393 394 Active Cell Death 395 Figure 3 Consequences of acute and chronic PKR-like endoplasmic reticulum (ER) kinase (PERK) activation. PERK has a kinase domain (K), and phos396 phorylates eukaryotic translation initiation factor 2 subunit alpha (eIF2a). In the acute phase, PERK-eIF2aP attenuates overloading the proteins into ER. On 397 chronic activation of PERK signaling, expression of activating transcription factor-4 (ATF4) is transnationally up-regulated, which regulates cell fate. GADD34 398 dephosphorylates eIF2aP to eIF2a, and protein translation is reinitiated. Expression of ATF4 causes oxidative stress. Proapoptotic transcription factor CHOP is 399 transcriptionally induced by ATF4, and its translation is also enhanced by ATF4. Death receptor 5 (DR5; official name TNFRSF10B) is a CHOP target gene, and 400 abundant DR5 protein forms oligomer at the Golgi apparatus, which activates caspase (Casp)8 without requirement of any ligand. Inhibitors of apoptosis 401 proteins (IAPs) are key cell death regulators in metazoans, through their suppression of caspases. Recent studies link PERK-eIF2aP-ATF4 signaling to IAP 402 regulation during ER stress. In response to chronic ER stress, IAP levels decrease specifically through the actions of PERK, but not IRE1 or ATF6 branches of the 403 unfolded protein response. The eIF2aP attenuates de novo IAP synthesis, particularly X-linked IAP, and ATF4’s transcriptional activity destabilizes extant XIAP 404 protein. 405 406 407 IRE1-centered protein-protein interactions can influence the cell death.45,47 These findings point to ATF4 as an important 408 sensitivity of IRE1 activation in response to ER stress. IRE1determinant in regulating cell fate during ER stress, with too 409 centered protein-protein interactions could also act conversely little and too much ATF4 both producing deleterious effects. 410 to influence cellular signaling processes and structures in One mechanism by which ATF4 can promote cell death 411 other cellular compartments during ER stress. is via transcriptional up-regulation of the GADD34 phos412 phatase (Figure 3). GADD34 dephosphorylates eIF2aP to 413 eIF2a.48 Dephosphorylation of eIF2aP removes the trans414 lational brake initially generated by PERK activation and Proapoptotic Consequences of PERK Signaling 415 leads to more protein synthesis and thereby protein folding 416 demands on the ER. Indeed, Han et al45 found that ATF4 PERK signaling down-regulates translation from most 417 mRNAs, thereby restricting de novo peptide loading onto the overexpression increased protein synthesis concomitant to 418 419 ER (Figure 1). This cytoprotective event by PERK to eIF2aP increasing cell death. Furthermore, chemical inhibition of 420 ½F3 occurs rapidly (Figure 3). Rare mRNAs bearing 50 upstream GADD34’s dephosphorylation of eIF2aP by the salubrinal 421 and guanabenz compounds protects cells from ER open reading frames, including the mRNAs encoding the 422 Q15 ATF4, ATF5, and CHOP transcriptional activators, are parastresseinduced cell death.49e51 423 doxically translated more efficiently during the phosphorylated A second mechanism by which ATF4 promotes cell death 424 state of eIF2a (Figure 3).42e44 ATF4’s transcriptional targets is via transcription of the proapoptotic Chop gene (official 425 name DDIT3), whose translation is also enhanced by eIF2aP include genes involved in amino acid metabolism, oxidore426 (Figure 3).16,43,44,52,53 By dual transcriptional and transductases required for disulfide bond formation in the ER, 427 Q16 several ubiquitin ligases, GADD34 phosphatase, and CHOP lational up-regulation, CHOP is highly enriched when PERK 428 45e47 is strongly activated. CHOP’s role as a proapoptotic trantranscription factor. ATF4-null mouse embryonic fibro429 scription factor has been clearly shown in vitro where CHOPblasts are sensitive to oxidative stress and require supplemental 430 431 null cells are resistant to cell death induced by the chemical reducing compounds for survival and growth in cell culture.46 432 ER toxins, tunicamycin, and thapsigargin.53 Several of Interestingly, ATF4 overexpression in mouse embryonic fi433 broblasts and neurons also evokes oxidative stress and increases CHOP’s transcriptional targets are implicated in apoptosis, 434
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Figure 4
A: Rhodopsin (Rho) is robustly degraded during retinal degeneration. Light micrographs of wild-type and P23H knock-in mouse retinas at postnatal (P) day 15. At P15, both rod outer segments (OSs) and rod inner segments (ISs) are shorter in RhoP23H/þ mice compared with those of the Rhoþ/þ mice, and significantly shortened in RhoP23H/P23H mice. The outer nuclear layer (ONL) is also significantly thinner in RhoP23H/P23H mice. Rhodopsin protein levels are significantly diminished in RhoP23H/P23H mice. Retinal protein lysates were collected from Rhoþ/þ, RhoP23H/þ, and RhoP23H/P23H mice at P15. Rhodopsin is detected by immunoblotting. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) served as a loading control. B: High prion protein (PrP) levels are maintained during prion infection. Hematoxylin and eosinestained hippocampal sections from mock- or prion-inoculated transgenic mice expressing human PrP reveal neuronal necrosis (arrowhead) and spongiform degeneration only in prion-infected mice. Total PrP levels (PrPC þ PrPSc) in brain are similar in mockand prion-infected mice by immunoblotting (20 mg protein per well). Samples treated with 100 mg/mL proteinase K (PK) reveal PK-resistant PrPSc only in prioninfected brain (100 mg protein per well). Actin served as a loading control (the actin bands are above the PrP in the undigested lanes). This blot was developed using monoclonal antibodies 3F4 against PrP (Millipore) and GT5412 against actin (Genetex). PrP contains two potential n-glycosylation sites and, thus, migrates as three bands corresponding to diglycosylated, monoglycosylated, or unglycosylated PrP. Scale bars: 10 mm (A); 50 mm (B).
including the apoptotic Bim (official name BCL2L11) and Puma (official name BBC3) Bcl-2 family genes,54,55 Trb3 (official name TAS2R13), and Dr5 (official name TNFRSF10B).29,56,57 DR5 can signal cell death by activating caspase-8.29,57 During ER stresseinduced cell death, DR5 protein accumulates in Golgi apparatus, where it oligomerizes, leading to activation of cytosolic caspase 8. Interestingly, DR5 mRNA is also down-regulated by IRE1-mediated RIDD, and the balance between the opposing effects of IRE1 and PERK on DR5 levels may tip whether UPR selects cell survival or cell death during ER stress.29 Some types of ER stresseinduced damage and cell death are unlikely to be mediated via CHOP induction. Comprehensive RNA-sequencing and microarray studies saw minimal transcriptional induction of previously identified apoptotic genes after forced Chop expression.45 Furthermore, forced CHOP expression itself does not trigger cell death in vitro,45,58 indicating that other proapoptotic hits are necessary for ER stresseinduced cell death. Inhibitors of apoptosis (IAPs) are key cell death regulators in metazoan organisms through their suppression of caspases.59 Recent studies link PERK-eIF2aP-ATF4 signaling to IAP regulation during ER stress. In response to chronic ER stress, IAP levels decrease significantly in many mammalian cell types, specifically through the actions of the
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PERK, but not IRE1 or ATF6, branches of the UPR.60e63 PERK signaling attenuates de novo X-linked IAP (XIAP) protein synthesis via eIF2aP and also promotes extant XIAP protein degradation by ATF4 transcriptional activity (Figure 3). In contrast, CHOP had no effect on XIAP levels. Loss of XIAP enhances sensitivity to ER stresseinduced cell death, and overexpression of XIAP protects cells from ER stress, and interestingly, synergizes with the absence of CHOP to induce even greater resistance to ER stresse induced cell death than Chop/ alone.58 These findings show that PERK-eIF2aP-ATF4 signaling promotes multiple proapoptotic hits within the cell, including the induction of CHOP and suppression of IAPs (Figure 3). These effects of chronic PERK signaling, therefore, generate a cellular milieu conducive for efficient caspase activation by removal of caspase inhibitors. The ability of IRE1 and PERK signaling to activate multiple distinct proapoptotic circuits provides attractive mechanisms to link ER stress to disease pathogenesis and progression. Physiological ER stresses vary tremendously with respect to their intensity and their cause (eg, hypoxia versus genetic mutation). Important questions for defining the role of UPR as disease mechanism include the following: Which UPR signaling events are activated by a physiological ER stress? What is the consequence of UPR
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Hiramatsu et al 621 activation in the cellular and tissue context of a specific 622 disease? In the subsequent sections, we examine how UPR 623 activation and function contribute to the pathogenesis of two 624 diseases associated with ER stress, retinitis pigmentosa and 625 prion infection. 626 627 628 Divergent Mechanisms of ER StresseInduced 629 Neurodegeneration 630 631 ER-Associated Degradation in Retinitis Pigmentosa 632 633 Retinitis pigmentosa is a human blinding disease arising 634 from photoreceptor cell death in the eye. Photoreceptors are 635 specialized sensory neurons that detect light and activate 636 retinal circuitry to transmit visual information to the brain. 637 Photoreceptors accomplish this feat using the visual 638 pigment, rhodopsin, a G-proteinecoupled transmembrane 639 receptor protein covalently linked to 11-cis-retinal.64 640 Rhodopsin is essential for photoreceptor function and sur641 vival, and rhodopsin knockout mice (Rho/) develop early 642 643 retinal degeneration.65,66 More than 100 rhodopsin muta644 tions have been identified in families with heritable types of 645 retinitis pigmentosa.67 Many of these mutations generate 646 misfolded rhodopsin proteins that are aggregation prone and 647 retained in the ER.24,68e71 Recent studies in mouse models 648 of retinitis pigmentosa have shed light into how the UPR in 649 photoreceptors copes with mutant rhodopsins and influences 650 the disease process. 651 The P23H rhodopsin mutation is the most common cause of 652 heritable retinitis pigmentosa in North America, and photore653 ceptors carrying the mutation generate misfolded rhodopsin 654 655 proteins that do not traffic normally to the rod photoreceptor 656 outer segment. A P23H rhodopsin knock-in mouse closely 657 mirrors the spatial distribution and temporal progression of 658 photoreceptor cell death and vision loss found in patients with 659 this mutation.72 Analysis of these mice indicates that these 660 photoreceptors use an unusual, customized UPR tailored to 661 cope with P23H rhodopsin.73 IRE1’s induction of XBP1s, and 662 the transcriptional up-regulation of ERAD by XBP1s, was 663 seen in photoreceptors expressing P23H rhodopsin.73 664 Concomitant with ERAD up-regulation, P23H rhodopsin 665 protein is found to be robustly ubiquitinated and almost 666 667 ½F4 entirely degraded in these photoreceptors73 (Figure 4A). In 668 contrast, other IRE1-mediated signaling events, including 669 c-Jun N-terminal kinase activation or RIDD, are not observed 670 in these photoreceptors.73 Furthermore, minimal activation of 671 the PERK signaling pathway is seen, with no changes in 672 ATF4, CHOP, or IAP levels in P23H rhodopsin-expressing 673 photoreceptors.73 These findings reveal that the dominant ef674 fect of UPR in photoreceptors of P23H rhodopsin knock-in 675 mice is the induction of ERAD to degrade and clear mutant 676 rhodopsin, which is accomplished through a preferential use of 677 the parts of the UPR regulating ERAD, such as IRE1’s in678 679 duction of XBP1. PERK’s proapoptotic functions through 680 modulation of ATF4, CHOP, and IAPs are not used in these 681 photoreceptors. Consistently, Chop/ fails to delay retinal 682
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degeneration in P23H rhodopsin knock-in photoreceptors, and in other genetically modified mouse lines expressing other rhodopsin mutations seen in retinitis pigmentosa.73e75 What drives photoreceptor cell death if PERK’s proapoptotic signals are not activated? Rhodopsin is essential for photoreceptor function, structure, development, and survival, and Rho/ mice develop early retinal degeneration.65,66 In P23H rhodopsin knock-in animals, rhodopsin protein degradation occurs as soon as photoreceptors are born, and loss of rhodopsin precedes any photoreceptor cell death (Figure 4A).73 Disruption of rhodopsin protein homeostasis by ERAD is likely to be a key trigger for photoreceptor cell death.
PERK Signaling in Prion Diseases Prion diseases are fatal neurodegenerative disorders arising from conversion of the normal cellular prion protein, PrPC, into a misfolded and self-templating conformer, PrPSc. PrPC Q17 Q18 is highly conserved among mammals and ubiquitously expressed, yet the functions attributed to PrPC are diverse and include maintenance of myelin, nomal synaptic function, and neuroprotection.76e79 PrPC is a glycosylphosphatidylinositolanchored glycoprotein that undergoes folding and posttranslational modifications within the ER and secretory pathway. In cell culture, PrPSc replication triggers ER stress, resulting in the aberrant accumulation of PrP in the cytosol and further enhancing the formation of PrPSc.80e82 ER stress and UPR activation have also been observed in prion infection in vivo83e85 as well as transgenic mice expressing mutant PrPC.86 Genetic and chemical modulation of different UPR pathways in prion-infected models has revealed intriguing and surprising differences from mutant rhodopsin models in the role of UPR signaling pathways in cellular degeneration. PrPC-to-PrPSc conversion and neurodegeneration are unchanged in mice deficient in neuronal Xbp1/ compared with controls.85 In contrast, genetic or chemical inhibition of PERK pathway signaling using GADD34 overexpression or the PERK inhibitor GSK2606414 ameliorates neuro- Q19 degeneration in prion-infected mice, whereas activating the PERK pathway using salubrinal worsens prion-associated neurotoxicity.83,84 These studies reveal a direct role for the PERK pathway in prion disease pathogenesis, and suggest that IRE1 signaling, at least through XBP1s generation, is dispensable in this process. How is the PERK signaling critical in the pathogenesis of prion disease, yet unnecessary for mutant rhodopsininduced cell death? One fundamental difference between these diseases is that prion conversion likely occurs on the cell membrane or in an endolysosomal compartment; thus, PrPSc escapes the misfolded protein clearance and degradation mechanisms triggered during UPR activation86 (Figure 4B). Indeed, levels of the PrPSc isoform increase substantially by the terminal stage of disease (Figure 4B). The accumulation of PrP in the brain likely causes chronic
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UPR in Disease Pathogenesis ER stress, leading to strong PERK signaling and its subsequent proapoptotic signaling cascade (Figure 2). In contrast, misfolded rhodopsin is degraded so quickly and efficiently (Figure 4A) that the strength and duration of ER stress do not increase to a threshold necessary for strong PERK activation. Thus, prion infection may represent a class of ER stresseassociated diseases in which PERK’s proapoptotic signaling output prevails when UPR protein quality control mechanisms fail to remove the misfolded proteins. Misfolded rhodopsins may represent another class of ER stresseassociated diseases in which UPR protein quality control mechanisms remove the misfolded proteins but, in doing so, disrupt vital cellular structures or processes required for cell viability.
Tailoring the UPR to Fit a Specific Disease The UPR signaling pathways are found in all cell types and activate broad transcriptional, translational, and posttranslational programs to help cells cope with ER stress. The PERK and IRE1 UPR pathways can promote cell death through multiple downstream effectors. Comparison of two ER stresseassociated diseases (retinitis pigmentosa and prion disease) reveals that different UPR signaling events are activated during pathogenesis of these diseases. Customization and tailoring of the UPR to fit a physiological ER stress and specific cell types are likely to occur in other ER stresseassociated disease processes.
Acknowledgment We thank Dr. Luke Wiseman (The Scripps Research Institute, La Jolla, CA) for his helpful comments.
References 1. Hetz C, Glimcher LH: Fine-tuning of the unfolded protein response: assembling the IRE1alpha interactome. Mol Cell 2009, 35:551e561 2. Cox JS, Shamu CE, Walter P: Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase. Cell 1993, 73:1197e1206 3. Shamu CE, Walter P: Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus. EMBO J 1996, 15:3028e3039 4. Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG, Ron D: IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 2002, 415:92e96 5. Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K: XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 2001, 107:881e891 6. Lu Y, Liang FX, Wang X: A synthetic biology approach identifies the mammalian UPR RNA ligase RtcB. Mol Cell 2014, 55:758e770 7. Jurkin J, Henkel T, Nielsen AF, Minnich M, Popow J, Kaufmann T, Heindl K, Hoffmann T, Busslinger M, Martinez J: The mammalian tRNA ligase complex mediates splicing of XBP1 mRNA and controls antibody secretion in plasma cells. EMBO J 2014, 33:2922e2936
The American Journal of Pathology
-
8. Kosmaczewski SG, Edwards TJ, Han SM, Eckwahl MJ, Meyer BI, Peach S, Hesselberth JR, Wolin SL, Hammarlund M: The RtcB RNA ligase is an essential component of the metazoan unfolded protein response. EMBO Rep 2014, 15:1278e1285 9. Lee AH, Iwakoshi NN, Glimcher LH: XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol 2003, 23:7448e7459 10. Shoulders MD, Ryno LM, Genereux JC, Moresco JJ, Tu PG, Wu C, Yates JR 3rd, Su AI, Kelly JW, Wiseman RL: Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments. Cell Rep 2013, 3:1279e1292 11. Yamamoto K, Yoshida H, Kokame K, Kaufman RJ, Mori K: Differential contributions of ATF6 and XBP1 to the activation of endoplasmic reticulum stress-responsive cis-acting elements ERSE, UPRE and ERSE-II. J Biochem 2004, 136:343e350 12. Yamamoto K, Sato T, Matsui T, Sato M, Okada T, Yoshida H, Harada A, Mori K: Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1. Dev Cell 2007, 13:365e376 13. Shaffer AL, Shapiro-Shelef M, Iwakoshi NN, Lee AH, Qian SB, Zhao H, Yu X, Yang L, Tan BK, Rosenwald A, Hurt EM, Petroulakis E, Sonenberg N, Yewdell JW, Calame K, Glimcher LH, Staudt LM: XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity 2004, 21:81e93 14. Wang ZV, Deng Y, Gao N, Pedrozo Z, Li DL, Morales CR, Criollo A, Luo X, Tan W, Jiang N, Lehrman MA, Rothermel BA, Lee AH, Lavandero S, Mammen PP, Ferdous A, Gillette TG, Scherer PE, Hill JA: Spliced X-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway. Cell 2014, 156:1179e1192 15. Harding HP, Zhang Y, Ron D: Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 1999, 397:271e274 16. Harding HP, Calfon M, Urano F, Novoa I, Ron D: Transcriptional and translational control in the Mammalian unfolded protein response. Annu Rev Cell Dev Biol 2002, 18:575e599 17. Ron D, Harding HP: Protein-folding homeostasis in the endoplasmic reticulum and nutritional regulation. Cold Spring Harb Perspect Biol 2012:4. pii: a013177 18. Haze K, Yoshida H, Yanagi H, Yura T, Mori K: Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell 1999, 10:3787e3799 19. Ye J, Rawson RB, Komuro R, Chen X, Dave UP, Prywes R, Brown MS, Goldstein JL: ER stress induces cleavage of membranebound ATF6 by the same proteases that process SREBPs. Mol Cell 2000, 6:1355e1364 20. Wu J, Rutkowski DT, Dubois M, Swathirajan J, Saunders T, Wang J, Song B, Yau GD, Kaufman RJ: ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev Cell 2007, 13:351e364 21. Yoshida H, Matsui T, Hosokawa N, Kaufman RJ, Nagata K, Mori K: A time-dependent phase shift in the mammalian unfolded protein response. Dev Cell 2003, 4:265e271 22. Aragon T, van Anken E, Pincus D, Serafimova IM, Korennykh AV, Rubio CA, Walter P: Messenger RNA targeting to endoplasmic reticulum stress signalling sites. Nature 2009, 457:736e740 23. Li H, Korennykh AV, Behrman SL, Walter P: Mammalian endoplasmic reticulum stress sensor IRE1 signals by dynamic clustering. Proc Natl Acad Sci U S A 2010, 107:16113e16118 24. Lin JH, Li H, Yasumura D, Cohen HR, Zhang C, Panning B, Shokat KM, Lavail MM, Walter P: IRE1 signaling affects cell fate during the unfolded protein response. Science 2007, 318:944e949 25. Tam AB, Koong AC, Niwa M: Ire1 has distinct catalytic mechanisms for XBP1/HAC1 splicing and RIDD. Cell Rep 2014, 9: 850e858
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Hiramatsu et al 26. Hollien J, Weissman JS: Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 2006, 313: 104e107 27. Hollien J, Lin JH, Li H, Stevens N, Walter P, Weissman JS: Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J Cell Biol 2009, 186:323e331 28. Wang XT, McCullough KD, Wang XJ, Carpenter G, Holbrook NJ: Oxidative stress-induced phospholipase C-gamma 1 activation enhances cell survival. J Biol Chem 2001, 276:28364e28371 29. Lu M, Lawrence DA, Marsters S, Acosta-Alvear D, Kimmig P, Mendez AS, Paton AW, Paton JC, Walter P, Ashkenazi A: Cell death: opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis. Science 2014, 345:98e101 30. Hur KY, So JS, Ruda V, Frank-Kamenetsky M, Fitzgerald K, Koteliansky V, Iwawaki T, Glimcher LH, Lee AH: IRE1alpha activation protects mice against acetaminophen-induced hepatotoxicity. J Exp Med 2012, 209:307e318 31. Cho JA, Lee AH, Platzer B, Cross BC, Gardner BM, De Luca H, Luong P, Harding HP, Glimcher LH, Walter P, Fiebiger E, Ron D, Kagan JC, Lencer WI: The unfolded protein response element IRE1alpha senses bacterial proteins invading the ER to activate RIG-I and innate immune signaling. Cell Host Microbe 2013, 13:558e569 32. So JS, Hur KY, Tarrio M, Ruda V, Frank-Kamenetsky M, Fitzgerald K, Koteliansky V, Lichtman AH, Iwawaki T, Glimcher LH, Lee AH: Silencing of lipid metabolism genes through IRE1alpha-mediated mRNA decay lowers plasma lipids in mice. Cell Metab 2012, 16:487e499 33. Tirasophon W, Lee K, Callaghan B, Welihinda A, Kaufman RJ: The endoribonuclease activity of mammalian IRE1 autoregulates its mRNA and is required for the unfolded protein response. Genes Dev 2000, 14:2725e2736 34. Upton JP, Wang L, Han D, Wang ES, Huskey NE, Lim L, Truitt M, McManus MT, Ruggero D, Goga A, Papa FR, Oakes SA: IRE1a cleaves select microRNAs during ER stress to derepress translation of proapoptotic Caspase-2. Science 2012, 338:818e822 35. Kimmig P, Diaz M, Zheng J, Williams CC, Lang A, Aragon T, Li H, Walter P: The unfolded protein response in fission yeast modulates stability of select mRNAs to maintain protein homeostasis. Elife 2012, 1:e00048 36. Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D: Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 2000, 287:664e666 37. Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K, Hori S, Kakizuka A, Ichijo H: ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev 2002, 16:1345e1355 38. Qiu Y, Mao T, Zhang Y, Shao M, You J, Ding Q, Chen Y, Wu D, Xie D, Lin X, Gao X, Kaufman RJ, Li W, Liu Y: A crucial role for RACK1 in the regulation of glucose-stimulated IRE1alpha activation in pancreatic beta cells. Sci Signal 2010, 3:ra7 39. Hetz C, Bernasconi P, Fisher J, Lee AH, Bassik MC, Antonsson B, Brandt GS, Iwakoshi NN, Schinzel A, Glimcher LH, Korsmeyer SJ: Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha. Science 2006, 312:572e576 40. Lisbona F, Rojas-Rivera D, Thielen P, Zamorano S, Todd D, Martinon F, Glavic A, Kress C, Lin JH, Walter P, Reed JC, Glimcher LH, Hetz C: BAX inhibitor-1 is a negative regulator of the ER stress sensor IRE1alpha. Mol Cell 2009, 33:679e691 41. He Y, Beatty A, Han X, Ji Y, Ma X, Adelstein RS, Yates JR 3rd, Kemphues K, Qi L: Nonmuscle myosin IIB links cytoskeleton to IRE1alpha signaling during ER stress. Dev Cell 2012, 23:1141e1152 42. Zhou D, Palam LR, Jiang L, Narasimhan J, Staschke KA, Wek RC: Phosphorylation of eIF2 directs ATF5 translational control in response to diverse stress conditions. J Biol Chem 2008, 283:7064e7073 43. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D: Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 2000, 6:1099e1108
8
44. Palam LR, Baird TD, Wek RC: Phosphorylation of eIF2 facilitates ribosomal bypass of an inhibitory upstream ORF to enhance CHOP translation. J Biol Chem 2011, 286:10939e10949 45. Han J, Back SH, Hur J, Lin YH, Gildersleeve R, Shan J, Yuan CL, Krokowski D, Wang S, Hatzoglou M, Kilberg MS, Sartor MA, Kaufman RJ: ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat Cell Biol 2013, 15: 481e490 46. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, Stojdl DF, Bell JC, Hettmann T, Leiden JM, Ron D: An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 2003, 11:619e633 47. Lange PS, Chavez JC, Pinto JT, Coppola G, Sun CW, Townes TM, Geschwind DH, Ratan RR: ATF4 is an oxidative stress-inducible, prodeath transcription factor in neurons in vitro and in vivo. J Exp Med 2008, 205:1227e1242 48. Novoa I, Zeng H, Harding HP, Ron D: Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol 2001, 153:1011e1022 49. Papandreou I, Denko NC, Olson M, Van Melckebeke H, Lust S, Tam A, Solow-Cordero DE, Bouley DM, Offner F, Niwa M, Koong AC: Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma. Blood 2011, 117:1311e1314 50. Tsaytler P, Harding HP, Ron D, Bertolotti A: Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis. Science 2011, 332:91e94 51. Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, Kaufman RJ, Ma D, Coen DM, Ron D, Yuan J: A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science 2005, 307:935e939 52. Lee HC, Chen YJ, Liu YW, Lin KY, Chen SW, Lin CY, Lu YC, Hsu PC, Lee SC, Tsai HJ: Transgenic zebrafish model to study translational control mediated by upstream open reading frame of human chop gene. Nucleic Acids Res 2011, 39:e139 53. Zinszner H, Kuroda M, Wang X, Batchvarova N, Lightfoot RT, Remotti H, Stevens JL, Ron D: CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev 1998, 12:982e995 54. Puthalakath H, O’Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND, Hughes PD, Michalak EM, McKimm-Breschkin J, Motoyama N, Gotoh T, Akira S, Bouillet P, Strasser A: ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 2007, 129:1337e1349 55. Cazanave SC, Elmi NA, Akazawa Y, Bronk SF, Mott JL, Gores GJ: CHOP and AP-1 cooperatively mediate PUMA expression during lipoapoptosis. Am J Physiol Gastrointest Liver Physiol 2010, 299: G236eG243 56. Ohoka N, Yoshii S, Hattori T, Onozaki K, Hayashi H: TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. EMBO J 2005, 24:1243e1255 57. Yamaguchi H, Wang HG: CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J Biol Chem 2004, 279:45495e45502 58. Hiramatsu N, Messah C, Han J, LaVail MM, Kaufman RJ, Lin JH: Translational and post-translational regulation of XIAP by eIF2a and ATF4 promotes ER stress-induced cell death during the unfolded protein response. Mol Biol Cell 2014, 25:1411e1420 59. Salvesen GS, Duckett CS: IAP proteins: blocking the road to death’s door. Nat Rev Mol Cell Biol 2002, 3:401e410 60. Chiang WC, Hiramatsu N, Messah C, Kroeger H, Lin JH: Selective activation of ATF6 and PERK endoplasmic reticulum stress signaling pathways prevent mutant rhodopsin accumulation. Invest Ophthalmol Vis Sci 2012, 53:7159e7166 61. Hiramatsu N, Joseph VT, Lin JH: Monitoring and manipulating mammalian unfolded protein response. Methods Enzymol 2011, 491: 183e198
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UPR in Disease Pathogenesis 62. Lin AM, Fang SF, Chao PL, Yang CH: Melatonin attenuates arseniteinduced apoptosis in rat brain: involvement of mitochondrial and endoplasmic reticulum pathways and aggregation of alpha-synuclein. J Pineal Res 2007, 43:163e171 63. Lin JH, Li H, Zhang Y, Ron D, Walter P: Divergent effects of PERK and IRE1 signaling on cell viability. PLoS One 2009, 4:e4170 64. Palczewski K: G protein-coupled receptor rhodopsin. Annu Rev Biochem 2006, 75:743e767 65. Lem J, Krasnoperova NV, Calvert PD, Kosaras B, Cameron DA, Nicolo M, Makino CL, Sidman RL: Morphological, physiological, and biochemical changes in rhodopsin knockout mice. Proc Natl Acad Sci U S A 1999, 96:736e741 66. Humphries MM, Rancourt D, Farrar GJ, Kenna P, Hazel M, Bush RA, Sieving PA, Sheils DM, McNally N, Creighton P, Erven A, Boros A, Gulya K, Capecchi MR, Humphries P: Retinopathy induced in mice by targeted disruption of the rhodopsin gene. Nat Genet 1997, 15:216e219 67. Rattner A, Sun H, Nathans J: Molecular genetics of human retinal disease. Annu Rev Genet 1999, 33:89e131 68. Illing ME, Rajan RS, Bence NF, Kopito RR: A rhodopsin mutant linked to autosomal dominant retinitis pigmentosa is prone to aggregate and interacts with the ubiquitin proteasome system. J Biol Chem 2002, 277:34150e34160 69. Sung CH, Schneider BG, Agarwal N, Papermaster DS, Nathans J: Functional heterogeneity of mutant rhodopsins responsible for autosomal dominant retinitis pigmentosa. Proc Natl Acad Sci U S A 1991, 88:8840e8844 70. Kaushal S, Khorana HG: Structure and function in rhodopsin, 7: point mutations associated with autosomal dominant retinitis pigmentosa. Biochemistry 1994, 33:6121e6128 71. Chiang WC, Messah C, Lin JH: IRE1 directs proteasomal and lysosomal degradation of misfolded rhodopsin. Mol Biol Cell 2012, 23:758e770 72. Sakami S, Maeda T, Bereta G, Okano K, Golczak M, Sumaroka A, Roman AJ, Cideciyan AV, Jacobson SG, Palczewski K: Probing mechanisms of photoreceptor degeneration in a new mouse model of the common form of autosomal dominant retinitis pigmentosa due to P23H opsin mutations. J Biol Chem 2011, 286:10551e10567 73. Chiang WC, Kroeger H, Sakami S, Messah C, Yasumura D, Matthes MT, Coppinger JA, Palczewski K, LaVail MM, Lin JH: Robust endoplasmic reticulum-associated degradation of rhodopsin precedes retinal degeneration. Mol Neurobiol 2014, [Epub ahead of print]
The American Journal of Pathology
-
74. Nashine S, Bhootada Y, Lewin AS, Gorbatyuk M: Ablation of C/EBP homologous protein does not protect T17M RHO mice from retinal degeneration. PLoS One 2013, 8:e63205 75. Adekeye A, Haeri M, Solessio E, Knox BE: Ablation of the proapoptotic genes chop or ask1 does not prevent or delay loss of visual function in a P23H transgenic mouse model of retinitis pigmentosa. PLoS One 2014, 9:e83871 76. Bremer J, Baumann F, Tiberi C, Wessig C, Fischer H, Schwarz P, Steele AD, Toyka KV, Nave KA, Weis J, Aguzzi A: Axonal prion protein is required for peripheral myelin maintenance. Nat Neurosci 2010, 13:310e318 77. Collinge J, Whittington MA, Sidle KC, Smith CJ, Palmer MS, Clarke AR, Jefferys JG: Prion protein is necessary for normal synaptic function. Nature 1994, 370:295e297 78. Steele AD, Lindquist S, Aguzzi A: The prion protein knockout mouse: a phenotype under challenge. Prion 2007, 1:83e93 79. Linden R, Martins VR, Prado MA, Cammarota M, Izquierdo I, Brentani RR: Physiology of the prion protein. Physiol Rev 2008, 88: 673e728 80. Hetz C, Castilla J, Soto C: Perturbation of endoplasmic reticulum homeostasis facilitates prion replication. J Biol Chem 2007, 282: 12725e12733 81. Orsi A, Fioriti L, Chiesa R, Sitia R: Conditions of endoplasmic reticulum stress favor the accumulation of cytosolic prion protein. J Biol Chem 2006, 281:30431e30438 82. Nunziante M, Ackermann K, Dietrich K, Wolf H, Gädtke L, Gilch S, Vorberg I, Groschup M, Schätzl HM: Proteasomal dysfunction and endoplasmic reticulum stress enhance trafficking of prion protein aggregates through the secretory pathway and increase accumulation of pathologic prion protein. J Biol Chem 2011, 286:33942e33953 83. Moreno JA: Sustained translational repression by eIF2[alpha]-P mediates prion neurodegeneration. Nature 2012, 485:507e511 84. Moreno JA: Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci Transl Med 2013, 5:206ra138 85. Hetz C: Unfolded protein response transcription factor XBP-1 does not influence prion replication or pathogenesis. Proc Natl Acad Sci U S A 2008, 105:757e762 86. Dametto P, Lakkaraju AK, Bridel C, Villiger L, O’Connor T, Herrmann US, Pelczar P, Rülicke T, McHugh D, Adili A, Aguzzi A: Neurodegeneration and unfolded-protein response in mice expressing a membrane-tethered flexible tail of PrP. PLoS One 2015, 10: e0117412
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ASIP COTRAN EARLY CAREER INVESTIGATOR AWARD LECTURE Multiple Mechanisms of Unfolded Protein ResponseeInduced Cell Death Q27
Nobuhiko Hiramatsu, Wei-Chieh Chiang, Timothy D. Kurt, Christina J. Sigurdson, and Jonathan H. Lin From the Department of Pathology, University of California-San Diego, La Jolla, California Accepted for publication March 26, 2015.
Q5
Address correspondence to Jonathan H. Lin, Department of Pathology, University of California-San Diego, 9500 Glitman Dr, La Jolla, CA 92093-0612. E-mail: jlin@ ucsd.edu.
Eukaryotic cells fold and assemble membrane and secreted proteins in the endoplasmic reticulum (ER), before delivery to other cellular compartments or the extracellular environment. Correctly folded proteins are released from the ER, and poorly folded proteins are retained until they achieve stable conformations; irreparably misfolded proteins are targeted for degradation. Diverse pathological insults, such as amino acid mutations, hypoxia, or infection, can overwhelm ER protein quality control, leading to misfolded protein buildup, causing ER stress. To cope with ER stress, eukaryotic cells activate the unfolded protein response (UPR) by increasing levels of ER protein-folding enzymes and chaperones, enhancing the degradation of misfolded proteins, and reducing protein translation. In mammalian cells, three ER transmembrane proteins, inositol-requiring enzyme-1 (IRE1; official name ERN1), PKR-like ER kinase (PERK; official name EIF2AK3), and activating transcription factor-6, control the UPR. The UPR signaling triggers a set of prodeath programs when the cells fail to successfully adapt to ER stress or restore homeostasis. ER stress and UPR signaling are implicated in the pathogenesis of diverse diseases, including neurodegeneration, cancer, diabetes, and inflammation. This review discusses the current understanding in both adaptive and apoptotic responses as well as the molecular mechanisms instigating apoptosis via IRE1 and PERK signaling. We also examine how IRE1 and PERK signaling may be differentially used during neurodegeneration arising in retinitis pigmentosa and prion infection. (Am J Pathol 2015, -: 1e9; http://dx.doi.org/10.1016/j.ajpath.2015.03.009)
Q6
The endoplasmic reticulum (ER) is an essential organelle responsible for folding of secreted and membrane proteins and lipid and sterol biosynthesis, and it is a major site of free calcium storage within the cell. Cells have evolved a unique homeostatic mechanism, termed the unfolded protein response (UPR), to ensure that the ER can adapt to changing environmental and physiological demands of its functions. In mammalian cells, the UPR is controlled by the ER resident transmembrane proteins, inositol-requiring enzyme-1 (IRE1; official name ERN1), PKR-like ER kinase (PERK; official name EIF2AK3), and activating transcription factor-6 (ATF6). IRE1 is a transmembrane protein that controls a UPR signal transduction pathway conserved from yeast to mammals 1 ½F1 (Figure 1). IRE1 bears a luminal domain coupled across the ER membrane to cytosolic kinase and endoribonuclease (RNase)
domains.1 In response to ER stress, IRE1 undergoes oligomeric assembly, transautophosphorylation by its kinase domain, and activation of its distal RNase activity.2,3 In metazoans, the RNase activity of activated IRE1 and the RtcB tRNA ligase splice out a small intron from the X-box binding protein-1 (Xbp1) mRNA to produce XBP1s transcription factor.4e8 Supported by NIH grants R01EY020846, R01NS069566, R01NS076896, and R01NS088485 and VA grant BX002284. Disclosures: None declared. The American Society for Investigative Pathology Cotran Early Career Investigator Award recognizes early career investigators with demonstrated excellence as an investigator with recently established or emerging independence and with a research focus leading to an improved understanding of the conceptual basis of disease. Jonathan H. Lin, recipient of the ASIP 2013 Cotran Early Career Investigator Award, delivered a lecture entitled Endoplasmic Reticulum Stress in Disease Pathogenesis on April 22, 2013, at the annual meeting of the American Society for Investigative Pathology in Boston, MA.
Copyright ª 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajpath.2015.03.009
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Endoplasmic reticulum (ER) stress activates inositol-requiring enzyme 1 (IRE1), PKR-like ER kinase (PERK), and activating transcription factor-6 (ATF6) intracellular signal transduction pathways of the unfolded protein response (UPR). In normal condition, the UPR transducers, IRE1, PERK, and ATF6, associate with BiP to prevent UPR. On accumulation of misfolded proteins in the ER lumen, BiP dissociates to activate UPR transducers. IRE1 bears a luminal domain coupled across the ER membrane to cytosolic kinase (K) and endoribonuclease (RNase) domains (R). In response to ER stress, IRE1 undergoes oligomeric assembly, transautophosphorylation by its kinase domain, activating its distal RNase activity. Activated IRE1 splices out small intron from the X-box binding protein-1 (Xbp1) mRNA to generate active transcription factor XBP1s. The PERK protein bears luminal domain coupled across the ER membrane to K. In response to ER stress, PERK dimerizes and subsequently activates its cytosolic kinase domain. PERK’s kinase recognizes and phosphorylates eukaryotic translation initiation factor 2 subunit alpha (eIF2a), leading to attenuation of global protein translation. ATF6 bears an ER-tethered transcription factor. In response to ER stress, ATF6 migrates from the ER to the Golgi apparatus, where site 1 and 2 proteases (S1P and S2P, respectively) cleave its luminal and transmembrane domains, and release the cytosolic portion of ATF6 containing the bZIP transcriptional activator domain. Cleaved ATF6 fragment translocates to the nucleus to serve as a transcription factor.
The transcriptional targets of XBP1 are highly enriched for ER-associated protein degradation (ERAD) factors, ER chaperones, and enzymes required for lipid biosynthesis and protein glycosylation across diverse mammalian cell types.9e14 Up-regulation of these molecules by IRE1-toXBP1s induction therefore enhances the ER’s capacity to better fold new proteins as well as target irreparably damaged proteins for retrotranslocation out of the ER for degradation by proteasomes in the cytosol (Figure 1). The ER transmembrane protein PERK regulates another UPR signaling pathway in metazoans15 (Figure 1). On ER stress, PERK oligomerizes and activates its cytosolic kinase domain.15 PERK’s kinase phosphorylates eukaryotic translation initiation factor 2 subunit alpha (eIF2a) on Ser51, inhibiting the guanine nucleotide exchange factor eIF2B, which converts inactive GDP-bound eIF2 to its active GTP form.15,16 Active eIF2 complex is needed to form the GTP-tRNAMet ternary complex required for translation initiation. Therefore, eIF2a phosphorylation leads to translation inhibition that helps alleviate ER stress by reducing the load of new polypeptides that require assembly and folding in the ER compartment.17 ATF6 bears an ER-tethered bZip transcription factor that regulates a third UPR signal transduction pathway18 (Figure 1). In response to ER stress, ATF6 migrates from the ER to the Golgi apparatus, where site 1 protease and site 2 protease cleave its luminal and transmembrane domains to release the cytosolic portion of ATF6.18,19 The cytosolic
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portion of ATF6 contains the bZIP transcriptional activator domain, and after cleavage, this ATF6 fragment migrates to the nucleus to transcriptionally up-regulate ER chaperones and ERAD components, thereby enhancing ER proteinfolding capacity and efficiency of ERAD.10,12,18,20 Interestingly, ATF6 also transcriptionally up-regulates Xbp1, thereby facilitating IRE1 signal transduction by increasing levels of IRE1’s RNase substrate, Xbp1 mRNA.21 Put together, these initial transcriptional and translational effects of IRE1, PERK, and ATF6 signaling help cells adapt to ER stress by enhancing the fidelity of protein folding, increasing the degradation of damaged/misfolded proteins, and suppressing new protein synthesis. However, if these actions fail to restore ER homeostasis and ER stress persists, UPR signaling consequently triggers maladaptive proapoptotic programs, many of which are specifically activated through the IRE1 and PERK pathways.
IRE1 Signaling Independent of XBP1: RIDD, c-Jun N-Terminal Kinase, and BCL2 Seminal mechanistic studies from the laboratory of Walter and colleagues have revealed that IRE1 undergoes dynamic conformational and functional changes as a function of the duration of ER stress. In response to acute ER stress, IRE1 quickly forms oligomeric clusters in the ER plane, but IRE1
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Consequences of acute and chronic inositol-requiring enzyme 1 (IRE1) activation. In response to acute endoplasmic reticulum (ER) stress, IRE1 undergoes oligomeric assembly, undergoes transautophosphorylation by its kinase domain, and activates its distal RNase activity. Activated IRE1’s RNase splices out a small intron from the X-box binding protein-1 (Xbp1) mRNA to produce the active transcription factor XBP1s. IRE1-to-XBP1s induction enhances the ER’s capacity by up-regulation of gene sets involved in ER-associated protein degradation (ERAD), ER chaperones, lipid biosynthesis, and protein glycosylation. In the chronic phase of IRE1 activation, IRE1’s RNase domain cleaves ER-targeted mRNAs in a phenomenon termed regulated IRE1-dependent mRNA decay (RIDD). Most RIDD-targeted mRNAs are disposed. In contrast, IRE1-dependent cleavage of the 30 untranslated region of BiP mRNA in Schizosaccharomyces pombe stabilizes BiP mRNA, thereby increasing BiP protein levels to cope with ER stress. There is likely a regulated IRE1-dependent mRNA stabilization (RIDS) rather than RIDD, which may be a new mode by which IRE1’s RNase positively regulates mRNAs. The TRAF2 adaptor protein binds to IRE1 and the MAPKKK ASK1 to activate downstream molecules such as c-Jun N-terminal kinase (JNK), p38, and extracellular signaleregulated kinase (ERK). However, it is unclear which phase of IRE1 activity can interact with TRAF2-ASK1. Angptl, ---; Ces, ---; Cyp, ---; DR5, death receptor 5.
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subsequently dissociates if ER stress persists (Figure 2).22,23 Interestingly, Xbp1 mRNA splicing only occurs during the acute phase.23e25 During the chronic phase of ER stress, IRE1’s RNase substrate specificity is altered to cleave primarily ER-targeted mRNAs in a process termed regulated IRE1-dependent mRNA decay (RIDD)26e28 (Figure 2). In contrast to Xbp1 mRNA, RIDD targets are not ligated after IRE1 cleavage, and most mRNA fragments cleaved through RIDD are degraded. RIDD’s physiological significance varies widely and can confer protective or proapoptotic effects, depending on the cellular function of the mRNA being targeted. RIDD-mediated cleavage of death receptor 5 (DR5) mRNA enhances cell survival during ER stress by reducing production of proapoptotic DR5 protein.29 RIDD-mediated cleavage of cytochrome P450 enzyme mRNAs in liver confers resistance to liver damage after acetaminophen overdose by preventing P450-mediated generation of hepatotoxic byproducts.30 The mRNA fragments produced by RIDD cleavage can trigger inflammation by engaging with the cytosolic RIG1 RNA virus innate immunity sensor.31 RIDD-mediated loss of lipid metabolism mRNAs can alter plasma lipid levels in mice.32 Ire1 mRNA itself is a RIDD substrate, and RIDD may act as an autoregulatory brake on IRE1 signaling by down-regulating Ire1 mRNA levels.33 miRNA precursors have also been identified as RIDD substrates in vitro.34 Disruption of miRNA maturation by RIDD cleavage may further affect multiple biological processes by modulating miRNA-mRNA interactions throughout the cell.
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Recently, IRE1’s RNase was found to cleave the 30 untranslated region of BiP mRNA in Schizosaccharomyces pombe, but this truncation surprisingly stabilized, rather than promoted, the decay of the remaining BiP mRNA, thereby increasing BiP protein levels during ER stress.35 Regulated IRE1-dependent mRNA stabilization, rather than RIDD, may be a new mode by which IRE1’s RNase positively regulates mRNAs (Figure 2). Recent biochemical studies have suggested that IRE1 uses RIDD at intense ER stress levels, whereas Xbp1 mRNA splicing is initiated at much lower levels of ER stress25 (Figure 2). IRE1’s decision to trigger RIDD, regulated IRE1-dependent mRNA stabilization, or Xbp-1 mRNA splicing may be dependent on the intensity of the stress and the ability of various cell types to respond to that stress. The IRE1 oligomeric clusters formed by ER stress also act as molecular scaffolds to recruit other proteins and nucleate the formation of stress signal transduction sites at the ER lipid bilayer22,23 (Figure 2). For example, TRAF2 adaptor protein binds to IRE1 as well as the ASK1 MAPKKK to activate cytosolic signaling kinases, such as C-Jun N-terminal kinase, p38, and extracellular signaleregulated kinase during ER stress36,37 (Figure 2). IRE1 also interacts with the RACK1 adaptor protein to recruit phosphatases to the ER membrane during ER stress.38 IRE1 forms protein-protein interactions with BCL2 family proteins, such as BAX and BAK, and the BI-1 BCL2 regulatory protein.39,40 IRE1 also binds cytoskeletal nonmuscle myosin II during ER stress.41 These
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373 Normal Acute Phase Chronic Phase 374 375 376 377 378 P 379 P K K PP K K PP K P P 380 P P P P 381 P 382 P eIF2α eIF2α Translation 383 eIF2α Attenuation 384 40S 385 60S GADD34 ATF4 Degradation IAPs 386 Casp 387 Translation Inactive Attenuation 388 389 CHOP Redox Golgi 390 Genes 391 DR5 392 Casp 393 394 Active Cell Death 395 Figure 3 Consequences of acute and chronic PKR-like endoplasmic reticulum (ER) kinase (PERK) activation. PERK has a kinase domain (K), and phos396 phorylates eukaryotic translation initiation factor 2 subunit alpha (eIF2a). In the acute phase, PERK-eIF2aP attenuates overloading the proteins into ER. On 397 chronic activation of PERK signaling, expression of activating transcription factor-4 (ATF4) is transnationally up-regulated, which regulates cell fate. GADD34 398 dephosphorylates eIF2aP to eIF2a, and protein translation is reinitiated. Expression of ATF4 causes oxidative stress. Proapoptotic transcription factor CHOP is 399 transcriptionally induced by ATF4, and its translation is also enhanced by ATF4. Death receptor 5 (DR5; official name TNFRSF10B) is a CHOP target gene, and 400 abundant DR5 protein forms oligomer at the Golgi apparatus, which activates caspase (Casp)8 without requirement of any ligand. Inhibitors of apoptosis 401 proteins (IAPs) are key cell death regulators in metazoans, through their suppression of caspases. Recent studies link PERK-eIF2aP-ATF4 signaling to IAP 402 regulation during ER stress. In response to chronic ER stress, IAP levels decrease specifically through the actions of PERK, but not IRE1 or ATF6 branches of the 403 unfolded protein response. The eIF2aP attenuates de novo IAP synthesis, particularly X-linked IAP, and ATF4’s transcriptional activity destabilizes extant XIAP 404 protein. 405 406 407 IRE1-centered protein-protein interactions can influence the cell death.45,47 These findings point to ATF4 as an important 408 sensitivity of IRE1 activation in response to ER stress. IRE1determinant in regulating cell fate during ER stress, with too 409 centered protein-protein interactions could also act conversely little and too much ATF4 both producing deleterious effects. 410 to influence cellular signaling processes and structures in One mechanism by which ATF4 can promote cell death 411 other cellular compartments during ER stress. is via transcriptional up-regulation of the GADD34 phos412 phatase (Figure 3). GADD34 dephosphorylates eIF2aP to 413 eIF2a.48 Dephosphorylation of eIF2aP removes the trans414 lational brake initially generated by PERK activation and Proapoptotic Consequences of PERK Signaling 415 leads to more protein synthesis and thereby protein folding 416 demands on the ER. Indeed, Han et al45 found that ATF4 PERK signaling down-regulates translation from most 417 mRNAs, thereby restricting de novo peptide loading onto the overexpression increased protein synthesis concomitant to 418 419 ER (Figure 1). This cytoprotective event by PERK to eIF2aP increasing cell death. Furthermore, chemical inhibition of 420 ½F3 occurs rapidly (Figure 3). Rare mRNAs bearing 50 upstream GADD34’s dephosphorylation of eIF2aP by the salubrinal 421 and guanabenz compounds protects cells from ER open reading frames, including the mRNAs encoding the 422 Q15 ATF4, ATF5, and CHOP transcriptional activators, are parastresseinduced cell death.49e51 423 doxically translated more efficiently during the phosphorylated A second mechanism by which ATF4 promotes cell death 424 state of eIF2a (Figure 3).42e44 ATF4’s transcriptional targets is via transcription of the proapoptotic Chop gene (official 425 name DDIT3), whose translation is also enhanced by eIF2aP include genes involved in amino acid metabolism, oxidore426 (Figure 3).16,43,44,52,53 By dual transcriptional and transductases required for disulfide bond formation in the ER, 427 Q16 several ubiquitin ligases, GADD34 phosphatase, and CHOP lational up-regulation, CHOP is highly enriched when PERK 428 45e47 is strongly activated. CHOP’s role as a proapoptotic trantranscription factor. ATF4-null mouse embryonic fibro429 scription factor has been clearly shown in vitro where CHOPblasts are sensitive to oxidative stress and require supplemental 430 431 null cells are resistant to cell death induced by the chemical reducing compounds for survival and growth in cell culture.46 432 ER toxins, tunicamycin, and thapsigargin.53 Several of Interestingly, ATF4 overexpression in mouse embryonic fi433 broblasts and neurons also evokes oxidative stress and increases CHOP’s transcriptional targets are implicated in apoptosis, 434
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Figure 4
A: Rhodopsin (Rho) is robustly degraded during retinal degeneration. Light micrographs of wild-type and P23H knock-in mouse retinas at postnatal (P) day 15. At P15, both rod outer segments (OSs) and rod inner segments (ISs) are shorter in RhoP23H/þ mice compared with those of the Rhoþ/þ mice, and significantly shortened in RhoP23H/P23H mice. The outer nuclear layer (ONL) is also significantly thinner in RhoP23H/P23H mice. Rhodopsin protein levels are significantly diminished in RhoP23H/P23H mice. Retinal protein lysates were collected from Rhoþ/þ, RhoP23H/þ, and RhoP23H/P23H mice at P15. Rhodopsin is detected by immunoblotting. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) served as a loading control. B: High prion protein (PrP) levels are maintained during prion infection. Hematoxylin and eosinestained hippocampal sections from mock- or prion-inoculated transgenic mice expressing human PrP reveal neuronal necrosis (arrowhead) and spongiform degeneration only in prion-infected mice. Total PrP levels (PrPC þ PrPSc) in brain are similar in mockand prion-infected mice by immunoblotting (20 mg protein per well). Samples treated with 100 mg/mL proteinase K (PK) reveal PK-resistant PrPSc only in prioninfected brain (100 mg protein per well). Actin served as a loading control (the actin bands are above the PrP in the undigested lanes). This blot was developed using monoclonal antibodies 3F4 against PrP (Millipore) and GT5412 against actin (Genetex). PrP contains two potential n-glycosylation sites and, thus, migrates as three bands corresponding to diglycosylated, monoglycosylated, or unglycosylated PrP. Scale bars: 10 mm (A); 50 mm (B).
including the apoptotic Bim (official name BCL2L11) and Puma (official name BBC3) Bcl-2 family genes,54,55 Trb3 (official name TAS2R13), and Dr5 (official name TNFRSF10B).29,56,57 DR5 can signal cell death by activating caspase-8.29,57 During ER stresseinduced cell death, DR5 protein accumulates in Golgi apparatus, where it oligomerizes, leading to activation of cytosolic caspase 8. Interestingly, DR5 mRNA is also down-regulated by IRE1-mediated RIDD, and the balance between the opposing effects of IRE1 and PERK on DR5 levels may tip whether UPR selects cell survival or cell death during ER stress.29 Some types of ER stresseinduced damage and cell death are unlikely to be mediated via CHOP induction. Comprehensive RNA-sequencing and microarray studies saw minimal transcriptional induction of previously identified apoptotic genes after forced Chop expression.45 Furthermore, forced CHOP expression itself does not trigger cell death in vitro,45,58 indicating that other proapoptotic hits are necessary for ER stresseinduced cell death. Inhibitors of apoptosis (IAPs) are key cell death regulators in metazoan organisms through their suppression of caspases.59 Recent studies link PERK-eIF2aP-ATF4 signaling to IAP regulation during ER stress. In response to chronic ER stress, IAP levels decrease significantly in many mammalian cell types, specifically through the actions of the
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PERK, but not IRE1 or ATF6, branches of the UPR.60e63 PERK signaling attenuates de novo X-linked IAP (XIAP) protein synthesis via eIF2aP and also promotes extant XIAP protein degradation by ATF4 transcriptional activity (Figure 3). In contrast, CHOP had no effect on XIAP levels. Loss of XIAP enhances sensitivity to ER stresseinduced cell death, and overexpression of XIAP protects cells from ER stress, and interestingly, synergizes with the absence of CHOP to induce even greater resistance to ER stresse induced cell death than Chop/ alone.58 These findings show that PERK-eIF2aP-ATF4 signaling promotes multiple proapoptotic hits within the cell, including the induction of CHOP and suppression of IAPs (Figure 3). These effects of chronic PERK signaling, therefore, generate a cellular milieu conducive for efficient caspase activation by removal of caspase inhibitors. The ability of IRE1 and PERK signaling to activate multiple distinct proapoptotic circuits provides attractive mechanisms to link ER stress to disease pathogenesis and progression. Physiological ER stresses vary tremendously with respect to their intensity and their cause (eg, hypoxia versus genetic mutation). Important questions for defining the role of UPR as disease mechanism include the following: Which UPR signaling events are activated by a physiological ER stress? What is the consequence of UPR
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Hiramatsu et al 621 activation in the cellular and tissue context of a specific 622 disease? In the subsequent sections, we examine how UPR 623 activation and function contribute to the pathogenesis of two 624 diseases associated with ER stress, retinitis pigmentosa and 625 prion infection. 626 627 628 Divergent Mechanisms of ER StresseInduced 629 Neurodegeneration 630 631 ER-Associated Degradation in Retinitis Pigmentosa 632 633 Retinitis pigmentosa is a human blinding disease arising 634 from photoreceptor cell death in the eye. Photoreceptors are 635 specialized sensory neurons that detect light and activate 636 retinal circuitry to transmit visual information to the brain. 637 Photoreceptors accomplish this feat using the visual 638 pigment, rhodopsin, a G-proteinecoupled transmembrane 639 receptor protein covalently linked to 11-cis-retinal.64 640 Rhodopsin is essential for photoreceptor function and sur641 vival, and rhodopsin knockout mice (Rho/) develop early 642 643 retinal degeneration.65,66 More than 100 rhodopsin muta644 tions have been identified in families with heritable types of 645 retinitis pigmentosa.67 Many of these mutations generate 646 misfolded rhodopsin proteins that are aggregation prone and 647 retained in the ER.24,68e71 Recent studies in mouse models 648 of retinitis pigmentosa have shed light into how the UPR in 649 photoreceptors copes with mutant rhodopsins and influences 650 the disease process. 651 The P23H rhodopsin mutation is the most common cause of 652 heritable retinitis pigmentosa in North America, and photore653 ceptors carrying the mutation generate misfolded rhodopsin 654 655 proteins that do not traffic normally to the rod photoreceptor 656 outer segment. A P23H rhodopsin knock-in mouse closely 657 mirrors the spatial distribution and temporal progression of 658 photoreceptor cell death and vision loss found in patients with 659 this mutation.72 Analysis of these mice indicates that these 660 photoreceptors use an unusual, customized UPR tailored to 661 cope with P23H rhodopsin.73 IRE1’s induction of XBP1s, and 662 the transcriptional up-regulation of ERAD by XBP1s, was 663 seen in photoreceptors expressing P23H rhodopsin.73 664 Concomitant with ERAD up-regulation, P23H rhodopsin 665 protein is found to be robustly ubiquitinated and almost 666 667 ½F4 entirely degraded in these photoreceptors73 (Figure 4A). In 668 contrast, other IRE1-mediated signaling events, including 669 c-Jun N-terminal kinase activation or RIDD, are not observed 670 in these photoreceptors.73 Furthermore, minimal activation of 671 the PERK signaling pathway is seen, with no changes in 672 ATF4, CHOP, or IAP levels in P23H rhodopsin-expressing 673 photoreceptors.73 These findings reveal that the dominant ef674 fect of UPR in photoreceptors of P23H rhodopsin knock-in 675 mice is the induction of ERAD to degrade and clear mutant 676 rhodopsin, which is accomplished through a preferential use of 677 the parts of the UPR regulating ERAD, such as IRE1’s in678 679 duction of XBP1. PERK’s proapoptotic functions through 680 modulation of ATF4, CHOP, and IAPs are not used in these 681 photoreceptors. Consistently, Chop/ fails to delay retinal 682
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degeneration in P23H rhodopsin knock-in photoreceptors, and in other genetically modified mouse lines expressing other rhodopsin mutations seen in retinitis pigmentosa.73e75 What drives photoreceptor cell death if PERK’s proapoptotic signals are not activated? Rhodopsin is essential for photoreceptor function, structure, development, and survival, and Rho/ mice develop early retinal degeneration.65,66 In P23H rhodopsin knock-in animals, rhodopsin protein degradation occurs as soon as photoreceptors are born, and loss of rhodopsin precedes any photoreceptor cell death (Figure 4A).73 Disruption of rhodopsin protein homeostasis by ERAD is likely to be a key trigger for photoreceptor cell death.
PERK Signaling in Prion Diseases Prion diseases are fatal neurodegenerative disorders arising from conversion of the normal cellular prion protein, PrPC, into a misfolded and self-templating conformer, PrPSc. PrPC Q17 Q18 is highly conserved among mammals and ubiquitously expressed, yet the functions attributed to PrPC are diverse and include maintenance of myelin, nomal synaptic function, and neuroprotection.76e79 PrPC is a glycosylphosphatidylinositolanchored glycoprotein that undergoes folding and posttranslational modifications within the ER and secretory pathway. In cell culture, PrPSc replication triggers ER stress, resulting in the aberrant accumulation of PrP in the cytosol and further enhancing the formation of PrPSc.80e82 ER stress and UPR activation have also been observed in prion infection in vivo83e85 as well as transgenic mice expressing mutant PrPC.86 Genetic and chemical modulation of different UPR pathways in prion-infected models has revealed intriguing and surprising differences from mutant rhodopsin models in the role of UPR signaling pathways in cellular degeneration. PrPC-to-PrPSc conversion and neurodegeneration are unchanged in mice deficient in neuronal Xbp1/ compared with controls.85 In contrast, genetic or chemical inhibition of PERK pathway signaling using GADD34 overexpression or the PERK inhibitor GSK2606414 ameliorates neuro- Q19 degeneration in prion-infected mice, whereas activating the PERK pathway using salubrinal worsens prion-associated neurotoxicity.83,84 These studies reveal a direct role for the PERK pathway in prion disease pathogenesis, and suggest that IRE1 signaling, at least through XBP1s generation, is dispensable in this process. How is the PERK signaling critical in the pathogenesis of prion disease, yet unnecessary for mutant rhodopsininduced cell death? One fundamental difference between these diseases is that prion conversion likely occurs on the cell membrane or in an endolysosomal compartment; thus, PrPSc escapes the misfolded protein clearance and degradation mechanisms triggered during UPR activation86 (Figure 4B). Indeed, levels of the PrPSc isoform increase substantially by the terminal stage of disease (Figure 4B). The accumulation of PrP in the brain likely causes chronic
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UPR in Disease Pathogenesis ER stress, leading to strong PERK signaling and its subsequent proapoptotic signaling cascade (Figure 2). In contrast, misfolded rhodopsin is degraded so quickly and efficiently (Figure 4A) that the strength and duration of ER stress do not increase to a threshold necessary for strong PERK activation. Thus, prion infection may represent a class of ER stresseassociated diseases in which PERK’s proapoptotic signaling output prevails when UPR protein quality control mechanisms fail to remove the misfolded proteins. Misfolded rhodopsins may represent another class of ER stresseassociated diseases in which UPR protein quality control mechanisms remove the misfolded proteins but, in doing so, disrupt vital cellular structures or processes required for cell viability.
Tailoring the UPR to Fit a Specific Disease The UPR signaling pathways are found in all cell types and activate broad transcriptional, translational, and posttranslational programs to help cells cope with ER stress. The PERK and IRE1 UPR pathways can promote cell death through multiple downstream effectors. Comparison of two ER stresseassociated diseases (retinitis pigmentosa and prion disease) reveals that different UPR signaling events are activated during pathogenesis of these diseases. Customization and tailoring of the UPR to fit a physiological ER stress and specific cell types are likely to occur in other ER stresseassociated disease processes.
Acknowledgment We thank Dr. Luke Wiseman (The Scripps Research Institute, La Jolla, CA) for his helpful comments.
References 1. Hetz C, Glimcher LH: Fine-tuning of the unfolded protein response: assembling the IRE1alpha interactome. Mol Cell 2009, 35:551e561 2. Cox JS, Shamu CE, Walter P: Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase. Cell 1993, 73:1197e1206 3. Shamu CE, Walter P: Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus. EMBO J 1996, 15:3028e3039 4. Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG, Ron D: IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 2002, 415:92e96 5. Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K: XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 2001, 107:881e891 6. Lu Y, Liang FX, Wang X: A synthetic biology approach identifies the mammalian UPR RNA ligase RtcB. Mol Cell 2014, 55:758e770 7. Jurkin J, Henkel T, Nielsen AF, Minnich M, Popow J, Kaufmann T, Heindl K, Hoffmann T, Busslinger M, Martinez J: The mammalian tRNA ligase complex mediates splicing of XBP1 mRNA and controls antibody secretion in plasma cells. EMBO J 2014, 33:2922e2936
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8. Kosmaczewski SG, Edwards TJ, Han SM, Eckwahl MJ, Meyer BI, Peach S, Hesselberth JR, Wolin SL, Hammarlund M: The RtcB RNA ligase is an essential component of the metazoan unfolded protein response. EMBO Rep 2014, 15:1278e1285 9. Lee AH, Iwakoshi NN, Glimcher LH: XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol 2003, 23:7448e7459 10. Shoulders MD, Ryno LM, Genereux JC, Moresco JJ, Tu PG, Wu C, Yates JR 3rd, Su AI, Kelly JW, Wiseman RL: Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments. Cell Rep 2013, 3:1279e1292 11. Yamamoto K, Yoshida H, Kokame K, Kaufman RJ, Mori K: Differential contributions of ATF6 and XBP1 to the activation of endoplasmic reticulum stress-responsive cis-acting elements ERSE, UPRE and ERSE-II. J Biochem 2004, 136:343e350 12. Yamamoto K, Sato T, Matsui T, Sato M, Okada T, Yoshida H, Harada A, Mori K: Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1. Dev Cell 2007, 13:365e376 13. Shaffer AL, Shapiro-Shelef M, Iwakoshi NN, Lee AH, Qian SB, Zhao H, Yu X, Yang L, Tan BK, Rosenwald A, Hurt EM, Petroulakis E, Sonenberg N, Yewdell JW, Calame K, Glimcher LH, Staudt LM: XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity 2004, 21:81e93 14. Wang ZV, Deng Y, Gao N, Pedrozo Z, Li DL, Morales CR, Criollo A, Luo X, Tan W, Jiang N, Lehrman MA, Rothermel BA, Lee AH, Lavandero S, Mammen PP, Ferdous A, Gillette TG, Scherer PE, Hill JA: Spliced X-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway. Cell 2014, 156:1179e1192 15. Harding HP, Zhang Y, Ron D: Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 1999, 397:271e274 16. Harding HP, Calfon M, Urano F, Novoa I, Ron D: Transcriptional and translational control in the Mammalian unfolded protein response. Annu Rev Cell Dev Biol 2002, 18:575e599 17. Ron D, Harding HP: Protein-folding homeostasis in the endoplasmic reticulum and nutritional regulation. Cold Spring Harb Perspect Biol 2012:4. pii: a013177 18. Haze K, Yoshida H, Yanagi H, Yura T, Mori K: Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell 1999, 10:3787e3799 19. Ye J, Rawson RB, Komuro R, Chen X, Dave UP, Prywes R, Brown MS, Goldstein JL: ER stress induces cleavage of membranebound ATF6 by the same proteases that process SREBPs. Mol Cell 2000, 6:1355e1364 20. Wu J, Rutkowski DT, Dubois M, Swathirajan J, Saunders T, Wang J, Song B, Yau GD, Kaufman RJ: ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev Cell 2007, 13:351e364 21. Yoshida H, Matsui T, Hosokawa N, Kaufman RJ, Nagata K, Mori K: A time-dependent phase shift in the mammalian unfolded protein response. Dev Cell 2003, 4:265e271 22. Aragon T, van Anken E, Pincus D, Serafimova IM, Korennykh AV, Rubio CA, Walter P: Messenger RNA targeting to endoplasmic reticulum stress signalling sites. Nature 2009, 457:736e740 23. Li H, Korennykh AV, Behrman SL, Walter P: Mammalian endoplasmic reticulum stress sensor IRE1 signals by dynamic clustering. Proc Natl Acad Sci U S A 2010, 107:16113e16118 24. Lin JH, Li H, Yasumura D, Cohen HR, Zhang C, Panning B, Shokat KM, Lavail MM, Walter P: IRE1 signaling affects cell fate during the unfolded protein response. Science 2007, 318:944e949 25. Tam AB, Koong AC, Niwa M: Ire1 has distinct catalytic mechanisms for XBP1/HAC1 splicing and RIDD. Cell Rep 2014, 9: 850e858
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Hiramatsu et al 26. Hollien J, Weissman JS: Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 2006, 313: 104e107 27. Hollien J, Lin JH, Li H, Stevens N, Walter P, Weissman JS: Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J Cell Biol 2009, 186:323e331 28. Wang XT, McCullough KD, Wang XJ, Carpenter G, Holbrook NJ: Oxidative stress-induced phospholipase C-gamma 1 activation enhances cell survival. J Biol Chem 2001, 276:28364e28371 29. Lu M, Lawrence DA, Marsters S, Acosta-Alvear D, Kimmig P, Mendez AS, Paton AW, Paton JC, Walter P, Ashkenazi A: Cell death: opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis. Science 2014, 345:98e101 30. Hur KY, So JS, Ruda V, Frank-Kamenetsky M, Fitzgerald K, Koteliansky V, Iwawaki T, Glimcher LH, Lee AH: IRE1alpha activation protects mice against acetaminophen-induced hepatotoxicity. J Exp Med 2012, 209:307e318 31. Cho JA, Lee AH, Platzer B, Cross BC, Gardner BM, De Luca H, Luong P, Harding HP, Glimcher LH, Walter P, Fiebiger E, Ron D, Kagan JC, Lencer WI: The unfolded protein response element IRE1alpha senses bacterial proteins invading the ER to activate RIG-I and innate immune signaling. Cell Host Microbe 2013, 13:558e569 32. So JS, Hur KY, Tarrio M, Ruda V, Frank-Kamenetsky M, Fitzgerald K, Koteliansky V, Lichtman AH, Iwawaki T, Glimcher LH, Lee AH: Silencing of lipid metabolism genes through IRE1alpha-mediated mRNA decay lowers plasma lipids in mice. Cell Metab 2012, 16:487e499 33. Tirasophon W, Lee K, Callaghan B, Welihinda A, Kaufman RJ: The endoribonuclease activity of mammalian IRE1 autoregulates its mRNA and is required for the unfolded protein response. Genes Dev 2000, 14:2725e2736 34. Upton JP, Wang L, Han D, Wang ES, Huskey NE, Lim L, Truitt M, McManus MT, Ruggero D, Goga A, Papa FR, Oakes SA: IRE1a cleaves select microRNAs during ER stress to derepress translation of proapoptotic Caspase-2. Science 2012, 338:818e822 35. Kimmig P, Diaz M, Zheng J, Williams CC, Lang A, Aragon T, Li H, Walter P: The unfolded protein response in fission yeast modulates stability of select mRNAs to maintain protein homeostasis. Elife 2012, 1:e00048 36. Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D: Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 2000, 287:664e666 37. Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K, Hori S, Kakizuka A, Ichijo H: ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev 2002, 16:1345e1355 38. Qiu Y, Mao T, Zhang Y, Shao M, You J, Ding Q, Chen Y, Wu D, Xie D, Lin X, Gao X, Kaufman RJ, Li W, Liu Y: A crucial role for RACK1 in the regulation of glucose-stimulated IRE1alpha activation in pancreatic beta cells. Sci Signal 2010, 3:ra7 39. Hetz C, Bernasconi P, Fisher J, Lee AH, Bassik MC, Antonsson B, Brandt GS, Iwakoshi NN, Schinzel A, Glimcher LH, Korsmeyer SJ: Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha. Science 2006, 312:572e576 40. Lisbona F, Rojas-Rivera D, Thielen P, Zamorano S, Todd D, Martinon F, Glavic A, Kress C, Lin JH, Walter P, Reed JC, Glimcher LH, Hetz C: BAX inhibitor-1 is a negative regulator of the ER stress sensor IRE1alpha. Mol Cell 2009, 33:679e691 41. He Y, Beatty A, Han X, Ji Y, Ma X, Adelstein RS, Yates JR 3rd, Kemphues K, Qi L: Nonmuscle myosin IIB links cytoskeleton to IRE1alpha signaling during ER stress. Dev Cell 2012, 23:1141e1152 42. Zhou D, Palam LR, Jiang L, Narasimhan J, Staschke KA, Wek RC: Phosphorylation of eIF2 directs ATF5 translational control in response to diverse stress conditions. J Biol Chem 2008, 283:7064e7073 43. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D: Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 2000, 6:1099e1108
8
44. Palam LR, Baird TD, Wek RC: Phosphorylation of eIF2 facilitates ribosomal bypass of an inhibitory upstream ORF to enhance CHOP translation. J Biol Chem 2011, 286:10939e10949 45. Han J, Back SH, Hur J, Lin YH, Gildersleeve R, Shan J, Yuan CL, Krokowski D, Wang S, Hatzoglou M, Kilberg MS, Sartor MA, Kaufman RJ: ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat Cell Biol 2013, 15: 481e490 46. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, Stojdl DF, Bell JC, Hettmann T, Leiden JM, Ron D: An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 2003, 11:619e633 47. Lange PS, Chavez JC, Pinto JT, Coppola G, Sun CW, Townes TM, Geschwind DH, Ratan RR: ATF4 is an oxidative stress-inducible, prodeath transcription factor in neurons in vitro and in vivo. J Exp Med 2008, 205:1227e1242 48. Novoa I, Zeng H, Harding HP, Ron D: Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol 2001, 153:1011e1022 49. Papandreou I, Denko NC, Olson M, Van Melckebeke H, Lust S, Tam A, Solow-Cordero DE, Bouley DM, Offner F, Niwa M, Koong AC: Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma. Blood 2011, 117:1311e1314 50. Tsaytler P, Harding HP, Ron D, Bertolotti A: Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis. Science 2011, 332:91e94 51. Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, Kaufman RJ, Ma D, Coen DM, Ron D, Yuan J: A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science 2005, 307:935e939 52. Lee HC, Chen YJ, Liu YW, Lin KY, Chen SW, Lin CY, Lu YC, Hsu PC, Lee SC, Tsai HJ: Transgenic zebrafish model to study translational control mediated by upstream open reading frame of human chop gene. Nucleic Acids Res 2011, 39:e139 53. Zinszner H, Kuroda M, Wang X, Batchvarova N, Lightfoot RT, Remotti H, Stevens JL, Ron D: CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev 1998, 12:982e995 54. Puthalakath H, O’Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND, Hughes PD, Michalak EM, McKimm-Breschkin J, Motoyama N, Gotoh T, Akira S, Bouillet P, Strasser A: ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 2007, 129:1337e1349 55. Cazanave SC, Elmi NA, Akazawa Y, Bronk SF, Mott JL, Gores GJ: CHOP and AP-1 cooperatively mediate PUMA expression during lipoapoptosis. Am J Physiol Gastrointest Liver Physiol 2010, 299: G236eG243 56. Ohoka N, Yoshii S, Hattori T, Onozaki K, Hayashi H: TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. EMBO J 2005, 24:1243e1255 57. Yamaguchi H, Wang HG: CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J Biol Chem 2004, 279:45495e45502 58. Hiramatsu N, Messah C, Han J, LaVail MM, Kaufman RJ, Lin JH: Translational and post-translational regulation of XIAP by eIF2a and ATF4 promotes ER stress-induced cell death during the unfolded protein response. Mol Biol Cell 2014, 25:1411e1420 59. Salvesen GS, Duckett CS: IAP proteins: blocking the road to death’s door. Nat Rev Mol Cell Biol 2002, 3:401e410 60. Chiang WC, Hiramatsu N, Messah C, Kroeger H, Lin JH: Selective activation of ATF6 and PERK endoplasmic reticulum stress signaling pathways prevent mutant rhodopsin accumulation. Invest Ophthalmol Vis Sci 2012, 53:7159e7166 61. Hiramatsu N, Joseph VT, Lin JH: Monitoring and manipulating mammalian unfolded protein response. Methods Enzymol 2011, 491: 183e198
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UPR in Disease Pathogenesis 62. Lin AM, Fang SF, Chao PL, Yang CH: Melatonin attenuates arseniteinduced apoptosis in rat brain: involvement of mitochondrial and endoplasmic reticulum pathways and aggregation of alpha-synuclein. J Pineal Res 2007, 43:163e171 63. Lin JH, Li H, Zhang Y, Ron D, Walter P: Divergent effects of PERK and IRE1 signaling on cell viability. PLoS One 2009, 4:e4170 64. Palczewski K: G protein-coupled receptor rhodopsin. Annu Rev Biochem 2006, 75:743e767 65. Lem J, Krasnoperova NV, Calvert PD, Kosaras B, Cameron DA, Nicolo M, Makino CL, Sidman RL: Morphological, physiological, and biochemical changes in rhodopsin knockout mice. Proc Natl Acad Sci U S A 1999, 96:736e741 66. Humphries MM, Rancourt D, Farrar GJ, Kenna P, Hazel M, Bush RA, Sieving PA, Sheils DM, McNally N, Creighton P, Erven A, Boros A, Gulya K, Capecchi MR, Humphries P: Retinopathy induced in mice by targeted disruption of the rhodopsin gene. Nat Genet 1997, 15:216e219 67. Rattner A, Sun H, Nathans J: Molecular genetics of human retinal disease. Annu Rev Genet 1999, 33:89e131 68. Illing ME, Rajan RS, Bence NF, Kopito RR: A rhodopsin mutant linked to autosomal dominant retinitis pigmentosa is prone to aggregate and interacts with the ubiquitin proteasome system. J Biol Chem 2002, 277:34150e34160 69. Sung CH, Schneider BG, Agarwal N, Papermaster DS, Nathans J: Functional heterogeneity of mutant rhodopsins responsible for autosomal dominant retinitis pigmentosa. Proc Natl Acad Sci U S A 1991, 88:8840e8844 70. Kaushal S, Khorana HG: Structure and function in rhodopsin, 7: point mutations associated with autosomal dominant retinitis pigmentosa. Biochemistry 1994, 33:6121e6128 71. Chiang WC, Messah C, Lin JH: IRE1 directs proteasomal and lysosomal degradation of misfolded rhodopsin. Mol Biol Cell 2012, 23:758e770 72. Sakami S, Maeda T, Bereta G, Okano K, Golczak M, Sumaroka A, Roman AJ, Cideciyan AV, Jacobson SG, Palczewski K: Probing mechanisms of photoreceptor degeneration in a new mouse model of the common form of autosomal dominant retinitis pigmentosa due to P23H opsin mutations. J Biol Chem 2011, 286:10551e10567 73. Chiang WC, Kroeger H, Sakami S, Messah C, Yasumura D, Matthes MT, Coppinger JA, Palczewski K, LaVail MM, Lin JH: Robust endoplasmic reticulum-associated degradation of rhodopsin precedes retinal degeneration. Mol Neurobiol 2014, [Epub ahead of print]
The American Journal of Pathology
-
74. Nashine S, Bhootada Y, Lewin AS, Gorbatyuk M: Ablation of C/EBP homologous protein does not protect T17M RHO mice from retinal degeneration. PLoS One 2013, 8:e63205 75. Adekeye A, Haeri M, Solessio E, Knox BE: Ablation of the proapoptotic genes chop or ask1 does not prevent or delay loss of visual function in a P23H transgenic mouse model of retinitis pigmentosa. PLoS One 2014, 9:e83871 76. Bremer J, Baumann F, Tiberi C, Wessig C, Fischer H, Schwarz P, Steele AD, Toyka KV, Nave KA, Weis J, Aguzzi A: Axonal prion protein is required for peripheral myelin maintenance. Nat Neurosci 2010, 13:310e318 77. Collinge J, Whittington MA, Sidle KC, Smith CJ, Palmer MS, Clarke AR, Jefferys JG: Prion protein is necessary for normal synaptic function. Nature 1994, 370:295e297 78. Steele AD, Lindquist S, Aguzzi A: The prion protein knockout mouse: a phenotype under challenge. Prion 2007, 1:83e93 79. Linden R, Martins VR, Prado MA, Cammarota M, Izquierdo I, Brentani RR: Physiology of the prion protein. Physiol Rev 2008, 88: 673e728 80. Hetz C, Castilla J, Soto C: Perturbation of endoplasmic reticulum homeostasis facilitates prion replication. J Biol Chem 2007, 282: 12725e12733 81. Orsi A, Fioriti L, Chiesa R, Sitia R: Conditions of endoplasmic reticulum stress favor the accumulation of cytosolic prion protein. J Biol Chem 2006, 281:30431e30438 82. Nunziante M, Ackermann K, Dietrich K, Wolf H, Gädtke L, Gilch S, Vorberg I, Groschup M, Schätzl HM: Proteasomal dysfunction and endoplasmic reticulum stress enhance trafficking of prion protein aggregates through the secretory pathway and increase accumulation of pathologic prion protein. J Biol Chem 2011, 286:33942e33953 83. Moreno JA: Sustained translational repression by eIF2[alpha]-P mediates prion neurodegeneration. Nature 2012, 485:507e511 84. Moreno JA: Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci Transl Med 2013, 5:206ra138 85. Hetz C: Unfolded protein response transcription factor XBP-1 does not influence prion replication or pathogenesis. Proc Natl Acad Sci U S A 2008, 105:757e762 86. Dametto P, Lakkaraju AK, Bridel C, Villiger L, O’Connor T, Herrmann US, Pelczar P, Rülicke T, McHugh D, Adili A, Aguzzi A: Neurodegeneration and unfolded-protein response in mice expressing a membrane-tethered flexible tail of PrP. PLoS One 2015, 10: e0117412
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