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Pore formation by GSDMD is the effector mechanism of pyroptosis Moritz M Gaidt & Veit Hornung
Pyroptosis is a unique, pro-inflammatory form of lytic cell death that is initiated by the activation of inflammatory caspases. The caspase substrate gasdermin D (GSDMD) plays a critical function in pyroptosis, yet the precise mode of action of this molecule in cell death execution remained unclear. Several recent reports, including a The EMBO Journal article, show that the caspasematured N-terminal fragment of GSDMD is recruited to lipid membranes to form pore-like structures, which constitutes the key effector mechanism of pyroptotic cell death.
See also: L Sborgi et al (August 2016)
T
he term pyroptosis (pyro greek for fire or fever) has been originally coined to describe the non-apoptotic, caspase-1-dependent cell death of Salmonella-infected macrophages that would alarm and recruit neighboring cells to the site of infection (Cookson & Brennan, 2001). Later it became apparent that the activation of caspase-1 to induce pyroptosis is controlled by a subset of PRRs that can induce inflammasome activation (e.g. NLRP3, AIM2 or NLRC4/NAIP). Upon recognition of their cognate ligands, these sensors seed the prion-like assembly of the inflammasome adapter ASC into a high molecular weight cytosolic complex to which caspase-1 becomes recruited and is activated by. Auto-processed caspase-1 then matures the cytokines IL-1b and IL-18 to render them bioactive and induce pyroptotic cell death. Besides this canonical inflammasome activation leading to caspase-1 maturation, other pro-inflammatory caspases,
murine caspase-11 and human caspase-4 and caspase-5, directly sense cytosolic LPS to induce pyroptosis and activate the NLRP3 inflammasome via the so-called noncanonical pathway (Broz & Dixit, 2016). Recently, GSDMD was found to be a substrate of inflammatory caspases, critically required for the induction of pyroptosis. Its maturation unleashed the pro-pyroptotic N-terminal fragment from auto-inhibition by the C-terminal part. With regard to inflammasome activation, it was found that GSDMD cleavage was strictly required for the secretion, but not for the maturation of caspase-1 and IL-1b (He et al, 2015; Kayagaki et al, 2015; Shi et al, 2015). However, the precise mode of action of GSDMD in pyroptosis induction remained to be determined. In a recent issue of the EMBO Journal, Sborgi et al (2016) show that the N-terminal part of GSDMD is capable of forming porelike structures in lipid membranes and thus constitutes the direct and sole effector of pyroptosis. Whereas under steady-state conditions full-length GSDMD was exclusively localized to the cytosol, the N-terminal part re-localized to membraneassociated and insoluble cytosolic fractions upon maturation. Using a cell-free approach, the authors further observed that the in vitro cleaved, recombinant N-terminal fragment of GSDMD could associate with liposomes, indicating that GSDMD itself could mediate its recruitment to membranes. Furthermore, cleaved GSDMD was capable of permeabilizing respective liposomes, thereby mediating the release of fluorophores with a Stokes radius of up to 8.5 nm. Utilizing cryoelectron microscopy, recombinant GSDMD could be visualized to form round, pore-like
structures on liposomes (20 nm inner diameter). Further characterization using atomic force microscopy elegantly demonstrated that these pores are indeed open and thus could allow the efflux of cytosolic content from pyroptosing cells. In summary, the work of Sborgi et al (2016) characterizes GSDMD as the sole pyroptosis effector molecule that is capable of building pores in lipid membranes. The highlighted publication by Sborgi et al (2016) is part of a series of reports on the role of GSDMD in pyroptosis (Aglietti et al, 2016; Ding et al, 2016; Liu et al, 2016). All studies come to the conclusion that the pore-forming property of the N-terminal fragment of GSDMD is the driver of pyroptotic cell death. Structural evidence supports the view that the C-terminal GSDMD domain exerts an auto-inhibitory function by targeting residues of the N-terminal part that are crucial for membrane association and pore formation (Ding et al, 2016). This auto-inhibition is overcome upon cleavage by inflammatory caspases, enabling membrane association of the Nterminal domain presumably utilizing the conserved, positively charged residues RKRR (Liu et al, 2016). Although results on the lipid-binding properties of GSDMD N-term differ substantially between individual studies, presumably owed to different experimental conditions, it can be concluded that the GSDMD N-term only associates with lipids of the inner leaflet of the plasma membrane, thus explaining why GSDMD only lyses from within the cell. Intriguingly, GSDMD also binds cardiolipin, a component of prokaryotic and also mitochondrial membranes, which may explain its proposed bactericidal in trans activity (Liu et al,
Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany. E-mail: [email protected] DOI 10.15252/embj.201695415 | Published online 29 August 2016
ª 2016 The Authors
The EMBO Journal
Vol 35 | No 20 | 2016
2167
The EMBO Journal
GSDMD pores induce pyroptosis
2016). However, further evidence that endogenous levels of GSDMD exert antibacterial functions in vivo is still required. Overall, the picture emerges that GSDMD cleavage by inflammatory caspases leads to
Moritz M Gaidt & Veit Hornung
see below). The influx of water driven by oncotic pressure induces cell swelling and pyroptotic rupture of the plasma membrane, which releases all cytosolic content (including LDH) (Fig 1).
translocation of the N-terminal fragment to the plasma membrane. Subsequent pore formation dissipates ion gradients and enables efflux of cytosolic proteins that fit through the pore (like IL-1b and caspase-1,
Bacterium
Binding of extracellular GSDMD to Cardiolipin
Permeabilization of bacteria Secretion of whole cytosolic content EXTRACELLULAR SPACE
Secretion of small proteins through pores?
Rupture of plasma membrane
Influx of H2O due to oncotic pressure
+
Covalent binding?
Na – Cl
Cell swelling
H2O H2O H2O H2O LDH
Membrane insertion? N
K+
? ?
GSDMD N-terminal fragments
CYTOSOL
GSDMD N-terminal fragment
IL-1β
Active Caspase-1
Pro-IL-1β
CELL MEMBRANE
Phosphatidylethanolamine Outer leaflet
Phosphatidylcholine Sphingomyelin Phosphatidylethanolamine
Inflammasome Pro-caspase-1
Inner leaflet
Active Caspase-1
Cleavage N
LPS Caspase-4 Caspase-5 Caspase-11
Phosphatidylinositol
RKRR N
C
Phosphatidylserine
? GSDMD N-terminal fragment
Gasdermin D GSDMD
Mitochondrial and bacterial membranes only Cardiolipin Cardiolipin?
Active Caspase-4 Caspase-5 Caspase-11
Figure 1. GSDMD-mediated pore formation induces pyroptotic cell death. Upon activation, inflammatory caspases cleave cytosolic GSDMD to release the auto-inhibition of the C-terminal part. The cleaved N-terminal fragment translocates to the plasma membrane to bind phospholipids of the inner leaflet presumably utilizing the conserved RKRR motif. At the same time, cardiolipin binding may enable recruitment of N-terminal GSDMD to mitochondria. Pore assembly at the plasma membrane enables breakdown of ion gradients and efflux of cytosolic proteins that are small enough to pass through the pores. Subsequently, water influx driven by oncotic pressure induces cell swelling and rupture of the plasma membrane, which releases the cytosolic content. Released N-terminal GSDMD may exhibit extracellular in trans bactericidal activity. Of note, occurrence of phospholipids at the plasma membrane does not represent the actual quantitative distribution.
2168
The EMBO Journal Vol 35 | No 20 | 2016
ª 2016 The Authors
Moritz M Gaidt & Veit Hornung
Besides exciting new insight into the biology of pyroptosis, these advances have important implications for our understanding of the inflammasome-associated IL-1b secretion. The overall inner diameter of the pore was determined to be around 15 nm (arithmetic mean of all four studies), and should theoretically suffice for the release of matured IL-1b and caspase-1 through the nascent pore independently of the subsequent rupture of the plasma membrane. Although formal proof is still missing, this notion is supported by observations made with pharmacological blockade of pyroptosis. As such, inhibition of pyroptosis downstream of pore formation by PEG and glycine treatment inhibits release of LDH but does not affect caspase-1 or IL-1b secretion (Fink & Cookson, 2006; Liao & Mogridge, 2009). It is important to note, however, that release through GSDMD pores is not the only form of IL-1b secretion. In fact, IL-1b can be secreted from cells that are not competent in pyroptosis (Conos et al, 2016), and from immune cells in the absence of pyroptosis (Gaidt et al, 2016; Wolf et al, 2016; Zanoni et al, 2016). In particular, after activation of the alternative inflammasome that omits the induction of pyroptosis (Gaidt et al, 2016), IL-1b secretion from viable cells has to rely on GSDMD-independent secretion pathways. Intriguingly, other members of the GSDM protein family have similar pro-pyroptotic effector functions (Shi et al, 2015). Since they are not controlled by inflammatory caspases, other post-translational modifications may regulate their activity. Considering their association with rare genetic diseases, it will be of special interest to determine their role in a potentially pyroptotic cell death in these conditions. In light of these new insights into biology of the GSDMD and the GSDM family, its members
ª 2016 The Authors
The EMBO Journal
GSDMD pores induce pyroptosis
can be attributed to the family of poreforming proteins. In summary, the here mentioned series of publications have finally shed light on the execution of pyroptosis by defining GSDMD as the sole effector molecule and by elucidating its pore-forming activity as the key mechanism of this pro-inflammatory cell death. Yet, further, especially structural, insights are required to address the biology of pore formation within the plasma membrane and the lipid-binding specification.
References Aglietti RA, Estevez A, Gupta A, Ramirez MG, Liu PS, Kayagaki N, Ciferri C, Dixit VM, Dueber EC (2016) GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes. Proc Natl Acad Sci USA 113: 7858 – 7863 Broz P, Dixit VM (2016) Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol 16: 407 – 420 Conos SA, Lawlor KE, Vaux DL, Vince JE, Lindqvist
inflammasome pathway. Immunity 44: 833 – 846 He W, Wan H, Hu L, Chen P, Wang X, Huang Z, Yang Z-H, Zhong C-Q, Han J (2015) Gasdermin D is an executor of pyroptosis and required for interleukin-1b secretion. Cell Res 25: 1285 – 1298 Kayagaki N, Stowe IB, Lee BL, O’Rourke K, Anderson K, Warming S, Cuellar T, Haley B, Roose-Girma M, Phung QT, Liu PS, Lill JR, Li H, Wu J, Kummerfeld S, Zhang J, Lee WP, Snipas SJ, Salvesen GS, Morris LX et al (2015) Caspase-11 cleaves gasdermin D for noncanonical inflammasome signaling. Nature 526: 666 – 671 Liao KC, Mogridge J (2009) Expression of Nlrp1b inflammasome components in human fibroblasts confers susceptibility to anthrax lethal toxin. Infect Immun 77: 4455 – 4462 Liu X, Zhang Z, Ruan J, Pan Y, Magupalli VG, Wu H, Lieberman J (2016) Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535: 153 – 158 Sborgi L, Rühl S, Mulvihill E, Pipercevic J, Heilig R, Stahlberg H, Farady CJ, Müller DJ, Broz P, Hiller
LM (2016) Cell death is not essential for
S (2016) GSDMD membrane pore formation
caspase-1-mediated interleukin-1b activation
constitutes the mechanism of pyroptotic cell
and secretion. Cell Death Differ doi: 10.1038/ cdd.2016.69 Cookson BT, Brennan MA (2001) Pro-inflammatory
death. EMBO J 35: 1766 – 1778 Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, Zhuang Y, Cai T, Wang F, Shao F (2015)
programmed cell death. Trends Microbiol 9:
Cleavage of GSDMD by inflammatory caspases
113 – 114
determines pyroptotic cell death. Nature 526:
Ding J, Wang K, Liu W, She Y, Sun Q, Shi J, Sun H, Wang D-C, Shao F (2016) Pore-forming activity
660 – 665 Wolf AJ, Reyes CN, Liang W, Becker C, Shimada K,
and structural autoinhibition of the gasdermin
Wheeler ML, Cho HC, Popescu NI, Coggeshall
family. Nature 535: 111 – 116
KM, Arditi M, Underhill DM (2016) Hexokinase
Fink SL, Cookson BT (2006) Caspase-1-dependent
is an innate immune receptor for the
pore formation during pyroptosis leads to
detection of bacterial peptidoglycan. Cell 116:
osmotic lysis of infected host macrophages. Cell
1 – 13
Microbiol 8: 1812 – 1825 Gaidt MM, Ebert TS, Chauhan D, Schmidt T, Schmid-Burgk JL, Rapino F, Robertson AAB,
Zanoni I, Tan Y, Di Gioia M, Broggi A, Ruan J, Shi J, Donado CA, Shao F, Wu H, Springstead JR, Kagan JC (2016) An endogenous caspase-11
Cooper MA, Graf T, Hornung V (2016) Human
ligand elicits interleukin-1 release from living
monocytes engage an alternative
dendritic cells. Science 352: 1232 – 1236
The EMBO Journal Vol 35 | No 20 | 2016
2169
Pore formation by GSDMD is the effector mechanism of pyroptosis Moritz M Gaidt & Veit Hornung
Pyroptosis is a unique, pro-inflammatory form of lytic cell death that is initiated by the activation of inflammatory caspases. The caspase substrate gasdermin D (GSDMD) plays a critical function in pyroptosis, yet the precise mode of action of this molecule in cell death execution remained unclear. Several recent reports, including a The EMBO Journal article, show that the caspasematured N-terminal fragment of GSDMD is recruited to lipid membranes to form pore-like structures, which constitutes the key effector mechanism of pyroptotic cell death.
See also: L Sborgi et al (August 2016)
T
he term pyroptosis (pyro greek for fire or fever) has been originally coined to describe the non-apoptotic, caspase-1-dependent cell death of Salmonella-infected macrophages that would alarm and recruit neighboring cells to the site of infection (Cookson & Brennan, 2001). Later it became apparent that the activation of caspase-1 to induce pyroptosis is controlled by a subset of PRRs that can induce inflammasome activation (e.g. NLRP3, AIM2 or NLRC4/NAIP). Upon recognition of their cognate ligands, these sensors seed the prion-like assembly of the inflammasome adapter ASC into a high molecular weight cytosolic complex to which caspase-1 becomes recruited and is activated by. Auto-processed caspase-1 then matures the cytokines IL-1b and IL-18 to render them bioactive and induce pyroptotic cell death. Besides this canonical inflammasome activation leading to caspase-1 maturation, other pro-inflammatory caspases,
murine caspase-11 and human caspase-4 and caspase-5, directly sense cytosolic LPS to induce pyroptosis and activate the NLRP3 inflammasome via the so-called noncanonical pathway (Broz & Dixit, 2016). Recently, GSDMD was found to be a substrate of inflammatory caspases, critically required for the induction of pyroptosis. Its maturation unleashed the pro-pyroptotic N-terminal fragment from auto-inhibition by the C-terminal part. With regard to inflammasome activation, it was found that GSDMD cleavage was strictly required for the secretion, but not for the maturation of caspase-1 and IL-1b (He et al, 2015; Kayagaki et al, 2015; Shi et al, 2015). However, the precise mode of action of GSDMD in pyroptosis induction remained to be determined. In a recent issue of the EMBO Journal, Sborgi et al (2016) show that the N-terminal part of GSDMD is capable of forming porelike structures in lipid membranes and thus constitutes the direct and sole effector of pyroptosis. Whereas under steady-state conditions full-length GSDMD was exclusively localized to the cytosol, the N-terminal part re-localized to membraneassociated and insoluble cytosolic fractions upon maturation. Using a cell-free approach, the authors further observed that the in vitro cleaved, recombinant N-terminal fragment of GSDMD could associate with liposomes, indicating that GSDMD itself could mediate its recruitment to membranes. Furthermore, cleaved GSDMD was capable of permeabilizing respective liposomes, thereby mediating the release of fluorophores with a Stokes radius of up to 8.5 nm. Utilizing cryoelectron microscopy, recombinant GSDMD could be visualized to form round, pore-like
structures on liposomes (20 nm inner diameter). Further characterization using atomic force microscopy elegantly demonstrated that these pores are indeed open and thus could allow the efflux of cytosolic content from pyroptosing cells. In summary, the work of Sborgi et al (2016) characterizes GSDMD as the sole pyroptosis effector molecule that is capable of building pores in lipid membranes. The highlighted publication by Sborgi et al (2016) is part of a series of reports on the role of GSDMD in pyroptosis (Aglietti et al, 2016; Ding et al, 2016; Liu et al, 2016). All studies come to the conclusion that the pore-forming property of the N-terminal fragment of GSDMD is the driver of pyroptotic cell death. Structural evidence supports the view that the C-terminal GSDMD domain exerts an auto-inhibitory function by targeting residues of the N-terminal part that are crucial for membrane association and pore formation (Ding et al, 2016). This auto-inhibition is overcome upon cleavage by inflammatory caspases, enabling membrane association of the Nterminal domain presumably utilizing the conserved, positively charged residues RKRR (Liu et al, 2016). Although results on the lipid-binding properties of GSDMD N-term differ substantially between individual studies, presumably owed to different experimental conditions, it can be concluded that the GSDMD N-term only associates with lipids of the inner leaflet of the plasma membrane, thus explaining why GSDMD only lyses from within the cell. Intriguingly, GSDMD also binds cardiolipin, a component of prokaryotic and also mitochondrial membranes, which may explain its proposed bactericidal in trans activity (Liu et al,
Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany. E-mail: [email protected] DOI 10.15252/embj.201695415 | Published online 29 August 2016
ª 2016 The Authors
The EMBO Journal
Vol 35 | No 20 | 2016
2167
The EMBO Journal
GSDMD pores induce pyroptosis
2016). However, further evidence that endogenous levels of GSDMD exert antibacterial functions in vivo is still required. Overall, the picture emerges that GSDMD cleavage by inflammatory caspases leads to
Moritz M Gaidt & Veit Hornung
see below). The influx of water driven by oncotic pressure induces cell swelling and pyroptotic rupture of the plasma membrane, which releases all cytosolic content (including LDH) (Fig 1).
translocation of the N-terminal fragment to the plasma membrane. Subsequent pore formation dissipates ion gradients and enables efflux of cytosolic proteins that fit through the pore (like IL-1b and caspase-1,
Bacterium
Binding of extracellular GSDMD to Cardiolipin
Permeabilization of bacteria Secretion of whole cytosolic content EXTRACELLULAR SPACE
Secretion of small proteins through pores?
Rupture of plasma membrane
Influx of H2O due to oncotic pressure
+
Covalent binding?
Na – Cl
Cell swelling
H2O H2O H2O H2O LDH
Membrane insertion? N
K+
? ?
GSDMD N-terminal fragments
CYTOSOL
GSDMD N-terminal fragment
IL-1β
Active Caspase-1
Pro-IL-1β
CELL MEMBRANE
Phosphatidylethanolamine Outer leaflet
Phosphatidylcholine Sphingomyelin Phosphatidylethanolamine
Inflammasome Pro-caspase-1
Inner leaflet
Active Caspase-1
Cleavage N
LPS Caspase-4 Caspase-5 Caspase-11
Phosphatidylinositol
RKRR N
C
Phosphatidylserine
? GSDMD N-terminal fragment
Gasdermin D GSDMD
Mitochondrial and bacterial membranes only Cardiolipin Cardiolipin?
Active Caspase-4 Caspase-5 Caspase-11
Figure 1. GSDMD-mediated pore formation induces pyroptotic cell death. Upon activation, inflammatory caspases cleave cytosolic GSDMD to release the auto-inhibition of the C-terminal part. The cleaved N-terminal fragment translocates to the plasma membrane to bind phospholipids of the inner leaflet presumably utilizing the conserved RKRR motif. At the same time, cardiolipin binding may enable recruitment of N-terminal GSDMD to mitochondria. Pore assembly at the plasma membrane enables breakdown of ion gradients and efflux of cytosolic proteins that are small enough to pass through the pores. Subsequently, water influx driven by oncotic pressure induces cell swelling and rupture of the plasma membrane, which releases the cytosolic content. Released N-terminal GSDMD may exhibit extracellular in trans bactericidal activity. Of note, occurrence of phospholipids at the plasma membrane does not represent the actual quantitative distribution.
2168
The EMBO Journal Vol 35 | No 20 | 2016
ª 2016 The Authors
Moritz M Gaidt & Veit Hornung
Besides exciting new insight into the biology of pyroptosis, these advances have important implications for our understanding of the inflammasome-associated IL-1b secretion. The overall inner diameter of the pore was determined to be around 15 nm (arithmetic mean of all four studies), and should theoretically suffice for the release of matured IL-1b and caspase-1 through the nascent pore independently of the subsequent rupture of the plasma membrane. Although formal proof is still missing, this notion is supported by observations made with pharmacological blockade of pyroptosis. As such, inhibition of pyroptosis downstream of pore formation by PEG and glycine treatment inhibits release of LDH but does not affect caspase-1 or IL-1b secretion (Fink & Cookson, 2006; Liao & Mogridge, 2009). It is important to note, however, that release through GSDMD pores is not the only form of IL-1b secretion. In fact, IL-1b can be secreted from cells that are not competent in pyroptosis (Conos et al, 2016), and from immune cells in the absence of pyroptosis (Gaidt et al, 2016; Wolf et al, 2016; Zanoni et al, 2016). In particular, after activation of the alternative inflammasome that omits the induction of pyroptosis (Gaidt et al, 2016), IL-1b secretion from viable cells has to rely on GSDMD-independent secretion pathways. Intriguingly, other members of the GSDM protein family have similar pro-pyroptotic effector functions (Shi et al, 2015). Since they are not controlled by inflammatory caspases, other post-translational modifications may regulate their activity. Considering their association with rare genetic diseases, it will be of special interest to determine their role in a potentially pyroptotic cell death in these conditions. In light of these new insights into biology of the GSDMD and the GSDM family, its members
ª 2016 The Authors
The EMBO Journal
GSDMD pores induce pyroptosis
can be attributed to the family of poreforming proteins. In summary, the here mentioned series of publications have finally shed light on the execution of pyroptosis by defining GSDMD as the sole effector molecule and by elucidating its pore-forming activity as the key mechanism of this pro-inflammatory cell death. Yet, further, especially structural, insights are required to address the biology of pore formation within the plasma membrane and the lipid-binding specification.
References Aglietti RA, Estevez A, Gupta A, Ramirez MG, Liu PS, Kayagaki N, Ciferri C, Dixit VM, Dueber EC (2016) GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes. Proc Natl Acad Sci USA 113: 7858 – 7863 Broz P, Dixit VM (2016) Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol 16: 407 – 420 Conos SA, Lawlor KE, Vaux DL, Vince JE, Lindqvist
inflammasome pathway. Immunity 44: 833 – 846 He W, Wan H, Hu L, Chen P, Wang X, Huang Z, Yang Z-H, Zhong C-Q, Han J (2015) Gasdermin D is an executor of pyroptosis and required for interleukin-1b secretion. Cell Res 25: 1285 – 1298 Kayagaki N, Stowe IB, Lee BL, O’Rourke K, Anderson K, Warming S, Cuellar T, Haley B, Roose-Girma M, Phung QT, Liu PS, Lill JR, Li H, Wu J, Kummerfeld S, Zhang J, Lee WP, Snipas SJ, Salvesen GS, Morris LX et al (2015) Caspase-11 cleaves gasdermin D for noncanonical inflammasome signaling. Nature 526: 666 – 671 Liao KC, Mogridge J (2009) Expression of Nlrp1b inflammasome components in human fibroblasts confers susceptibility to anthrax lethal toxin. Infect Immun 77: 4455 – 4462 Liu X, Zhang Z, Ruan J, Pan Y, Magupalli VG, Wu H, Lieberman J (2016) Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535: 153 – 158 Sborgi L, Rühl S, Mulvihill E, Pipercevic J, Heilig R, Stahlberg H, Farady CJ, Müller DJ, Broz P, Hiller
LM (2016) Cell death is not essential for
S (2016) GSDMD membrane pore formation
caspase-1-mediated interleukin-1b activation
constitutes the mechanism of pyroptotic cell
and secretion. Cell Death Differ doi: 10.1038/ cdd.2016.69 Cookson BT, Brennan MA (2001) Pro-inflammatory
death. EMBO J 35: 1766 – 1778 Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, Zhuang Y, Cai T, Wang F, Shao F (2015)
programmed cell death. Trends Microbiol 9:
Cleavage of GSDMD by inflammatory caspases
113 – 114
determines pyroptotic cell death. Nature 526:
Ding J, Wang K, Liu W, She Y, Sun Q, Shi J, Sun H, Wang D-C, Shao F (2016) Pore-forming activity
660 – 665 Wolf AJ, Reyes CN, Liang W, Becker C, Shimada K,
and structural autoinhibition of the gasdermin
Wheeler ML, Cho HC, Popescu NI, Coggeshall
family. Nature 535: 111 – 116
KM, Arditi M, Underhill DM (2016) Hexokinase
Fink SL, Cookson BT (2006) Caspase-1-dependent
is an innate immune receptor for the
pore formation during pyroptosis leads to
detection of bacterial peptidoglycan. Cell 116:
osmotic lysis of infected host macrophages. Cell
1 – 13
Microbiol 8: 1812 – 1825 Gaidt MM, Ebert TS, Chauhan D, Schmidt T, Schmid-Burgk JL, Rapino F, Robertson AAB,
Zanoni I, Tan Y, Di Gioia M, Broggi A, Ruan J, Shi J, Donado CA, Shao F, Wu H, Springstead JR, Kagan JC (2016) An endogenous caspase-11
Cooper MA, Graf T, Hornung V (2016) Human
ligand elicits interleukin-1 release from living
monocytes engage an alternative
dendritic cells. Science 352: 1232 – 1236
The EMBO Journal Vol 35 | No 20 | 2016
2169
