DNA AND CELL BIOLOGY Volume 33, Number 11, 2014 ª Mary Ann Liebert, Inc. Pp. 739–742 DOI: 10.1089/dna.2014.2567
DNACB BITS
Mitophagy in Viral Infections Mao Xia, Gang Meng, Min Li, and Jiwu Wei
Antiviral innate immune responses and apoptosis are the two major factors limiting viral infections. Successful viral infection requires the virus to take advantage of the cellular machinery to bypass cellular defenses. Accumulated evidences show that autophagy plays a crucial role in cell-to-virus interaction. Here, we focus on how viruses subvert mitophagy to favor viral replication by mitigating innate immune responses and apoptotic signaling.
Autophagy and Viral Infections
A
utophagy is a highly conserved homeostatic process, which allows cells to recycle their components and to remove dysfunctional organelles. A hallmark in this process is the formation of the double-membrane vesicles packing components targeted for lysosomal degradation (Deretic and Levine, 2009; Zhang and Ney, 2009; Geisler et al., 2010). There are at least three different patterns of autophagy, including microautophagy, chaperone-mediated autophagy, and macroautophagy (Crotzer and Blum, 2010; Li et al., 2011). Autophagy and/or autophagy-related proteins can be both proviral and antiviral factors depending on viral subtypes (Kudchodkar and Levine, 2009). Recent works show that autophagy is involved in the regulation of inflammation and constitutes an essential innate responsive mechanism defending pathogens in primitive eukaryotic cells (Kudchodkar and Levine, 2009; Deretic, 2012). Autophagy can engulf bacteria and viruses for lysosomal degradation (Levine, 2005; Knodler and Celli, 2011; Wild et al., 2011). Moreover, autophagy is also required for presenting viral antigens to major histocompatibility complex class II, leading to the activation of adaptive immunity (Hayward and Dinesh-Kumar, 2010). Interestingly, some viruses have evolved countermeasures to escape the antiviral properties of autophagy. For instance, matrix protein 2 of influenza A virus and Nef protein of human immunodeficiency virus inhibit the maturation of autophagosomes into autolysosomes by targeting beclin1 (Gannage et al., 2009; Kyei et al., 2009; Rossman and Lamb, 2009). Herpes simplex virus 1 restrains early stage of autophagic process through its Us 11 protein interacting with the protein kinase PKR (Lussignol et al., 2013). In contrast, some viruses can benefit from autophagy for their infections. Several families of RNA viruses may subvert autophagy for their replication by targeting immunityassociated GTPase family M (IRGM) (Gregoire et al., 2011). In addition, some viruses utilize autophagic mechanisms for enhanced viral transmission and replication to be even more
devastating, such as dengue virus (Heaton and Randall, 2011), hepatitis C virus (Shrivastava et al., 2011), poliovirus (Taylor and Kirkegaard, 2007), coronaviruses (Maier and Britton, 2012), chikungunya virus ( Joubert et al., 2012), and adenovirus (Rodriguez-Rocha et al., 2011). Mitophagy Promotes Viral Replication by Mitigating Antiviral Immune Responses
Mitophagy is known as a process of the selective engulfment of mitochondria by autophagosomes and their subsequent degradation by lysosomes (Kim et al., 2007), which functions as selective removal of damaged mitochondria ( Jin and Youle, 2012). Mitophagy occurs after recognition of altered mitochondria by some autophagic receptors, such as SQSTM1, ATG32, or NIX (Zhang and Ney, 2009; Geisler et al., 2010; Aoki et al., 2011). The crucial role of mitophagy in manipulation of viral infections is now getting clarified. Previous studies have observed mitophagy in cells infected by seasonal influenza A virus (Lupfer et al., 2013), hepatitis C virus (Kim et al., 2013b, 2014), and hepatitis B virus (Kim et al., 2013a). Following seasonal influenza A virus infection, receptor interacting protein kinase 2 (RIPK2)-mediated mitophagy reduces immunopathology by negatively regulating activation of NOD-like receptor family pyrin-containing domain protein 3 (NLRP3) signaling and inflammation (Lupfer et al., 2013). We have recently reported that measles virus Edmonston vaccine strain (MV-Edm) infection induces mitophagy in nonsmall cell lung cancer (NSCLC) cells leading to enhanced viral replication (Xia et al., 2014a). While MV-Edm infection induces innate immune responses by means of activation of DDX58/MAVS, it in parallel stimulates SQSTM1mediated mitophagy to degrade mitochondrion-tethered mitochondrial antiviral signaling protein (MAVS), a key adaptor protein of DDX58/IFIH1 signaling, and thus attenuates antiviral immune responses (Fig. 1). In this process, SQSTM1 plays a critical role in tipping the balance of antiviral or proviral roles of autophagy following MV-Edm
Jiangsu Key Laboratory of Molecular Medicine, Medical School, The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
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FIG. 1. Measles virus Edmonston vaccine strain (MV-Edm) subverts mitophagy to attenuate both innate immune responses and apoptosis. In this model, antiviral innate immunity and apoptosis are countermeasures limiting MV-Edm infections (antiviral path). MV-Edm subverts mitophagy to bypass these restrictions by two different mechanisms: mitophagy-mediated reduction of mitochondrion-tethered mitochondrial antiviral signaling protein (MAVS) and mitophagy-mediated reduction of cytochromecrelease (proviralpath).SQSTM1mayplaya crucial role in tipping the balance of antiviral or proviral functions of autophagy enhancing replication of MV-Edm, as it mediates mitophagy. infection. Of note, many previous studies show that SQSTM1 is upregulated in many cancers (Thompson et al., 2003; Duran et al., 2008; Mathew et al., 2009), which might explain why oncolytic viruses preferentially replicate in cancers. The induction of mitophagy by MV-Edm remains to be determined. It is possible that MV-Edm causes mitochondrial dysfunction by not yet well-defined mechanisms, thereby targeting mitochondria toward autophagic degradation. Mitochondrial dynamics also regulate antiviral innate immune responses. Mitochondrial fusion may increase the interaction of key factors such as MAVS in signaling of immune responses, and mitochondrial fission may mitigate these pathways (Castanier et al., 2010; West et al., 2011; Lartigue and Faustin, 2013). Given that IRGM contributes to proviral autophagy following measles virus infection (Gregoire et al., 2011) and that IRGM is implicated in the regulation of mitochondrial fission (Singh et al., 2010), it remains to be clarified whether IRGM primes infected cells for mitophagy by disrupting mitochondria dynamics. Mitophagy Favors Viral Replication by Attenuation of Apoptosis
Apoptosis is another crucial mechanism by which hosts defend themselves against viral infection. Since self-destruction may restrict viral replication and spread. However, viruses evolve various mechanisms to delay or prevent apoptosis.
XIA ET AL.
Recent studies unveil various cross talks between autophagy and apoptosis. It has been shown that autophagy inhibits apoptosis by preventing the activation of Bid or degrading active caspase-8 by Beclin 1 (Djavaheri-Mergny et al., 2010). Cleaved ATG5 by calpains translocates to mitochondria and interacts Bcl-xL leading to controlled cytochrome c release (Giansanti et al., 2011). Bcl-2 or Bcl-xL inhibits the proautophagic activity of Beclin 1 by binding to Beclin 1 (Maiuri et al., 2007). In line with these, autophagy can be utilized by viruses to counteract apoptosis. For instance, autophagy induced by chikungunya virus delays caspase-dependent cell death by the IRE1a–XBP-1 pathway interaction with ROSmediated mTOR inhibition ( Joubert et al., 2012), and autophagy induced by flavivirus NS4A protein protects epithelial cells from cell death (McLean et al., 2011). As mitochondria are regarded to function as the central executioner in apoptotic pathways (Estaquier et al., 2012), it is plausible that mitophagy may participate in the modulation of apoptosis. Indeed, Bnip3-induced mitophagy negatively regulates cytochrome c release capacity by mitophagic degradation of mitochondria before dysfunction (i.e., mitochondrial membrane permeability transition, depolarization, and release of cytochrome c), which results in decreased apoptosis (Zhu et al., 2013). Another study shows that mitophagy eliminates damaged mitochondria and thus reduces cytochrome c release to cytoplasm under heat shock (Yang et al., 2010). Recent studies also unveil the role of mitophagy in controlling apoptosis following viral infections. We find that mitophagy induced by MV-Edm switches cell death from apoptosis to necrosis in NSCLCs (Xia et al., 2014b). In addition to attenuation of antiviral immunity, mitophagy is also utilized by MV-Edm to eliminate defective mitochondria before cytochrome c is released, which results in decreased apoptosis following viral infection and therefore sustains viral replication in NSCLCs (Fig. 1). Several other studies show that HBV and HCV induce Drp1-mediated mitochondrial fission (mitochondrial fragmentation) and Parkin-dependent mitophagy, which attenuate apoptosis by reducing cytochrome c release and may have significant contribution in persisting viral infection (Kim et al., 2013a, 2013b, 2014). An Introduction of Measles Virus Edmonston Vaccine Strain
Measles virus is a negative-sense single-strand RNA paramyxovirus. The attenuated strains of the Edmonston vaccine lineage (MV-Edm) have been used for vaccination over 50 years with excellent safety records (Blechacz et al., 2006). In the past decades, MV-Edm and its genetic engineered substrains has been proved as promising oncolytic viruses against a number of tumor types, including ovarian cancer, glioma, myeloma, mesothelioma, adult brain tumor, and lymphoma (Russell et al., 2012). As an excellent oncolytic virus with safety records, MV-Edm has been investigated in several clinical trials and holds promising for advanced cancer patients (Russell and Peng, 2009; Russell et al., 2012). MVEdm enters cells via its cognate membrane-bound receptor CD46, which has been shown overexpressed on tumor cells (Msaouel et al., 2009). It has also been shown that measles virus could promote proviral autophagy by means of IRGMdependent pathway (Gregoire et al., 2011). Autophagosomal formation can be triggered by MV-Edm at very early stage
MITOPHAGY IN VIRAL INFECTIONS
during infection through a CD46-Cyt-1/GOPC pathway and matures into autolysosomes (Meiffren et al., 2010). At the late stage following infection, MV-Edm protein C contributes to sustain autophagy for viral infectivity (Richetta et al., 2013). Perspectives
Mitophagy favors measles virus replication by two different ways: mitophagy-mediated reduction of mitochondriontethered MAVS and mitophagy-mediated reduction of cytochrome c release. It deserves further intensive investigations to clarify if such mechanisms are also commonly subverted by other viruses. This will be of great interest not only for designing antiviral strategies but also for oncolytic virotherapies. Acknowledgments
This work was supported by the National Natural Science Foundation of China (81071860 and 81172143), Jiangsu Special Program for Clinical Medical Science and Technology (BL2014054), and the State Key Laboratory of Pharmaceutical Biotechnology (KF-GN-201301). Disclosure Statement
The authors have no conflicts of interest. References
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Giansanti, V., Torriglia, A., and Scovassi, A.I. (2011). Conversation between apoptosis and autophagy: ‘‘Is it your turn or mine?’’. Apoptosis 16, 321–333. Gregoire, I.P., Richetta, C., Meyniel-Schicklin, L., Borel, S., Pradezynski, F., Diaz, O., et al. (2011). IRGM is a common target of RNA viruses that subvert the autophagy network. PLoS Pathog 7, e1002422. Hayward, A.P., and Dinesh-Kumar, S.P. (2010). Special delivery for MHC II via autophagy. Immunity 32, 587–590. Heaton, N.S., and Randall, G. (2011). Dengue virus and autophagy. Viruses 3, 1332–1341. Jin, S.M., and Youle, R.J. (2012). PINK1- and Parkin-mediated mitophagy at a glance. J Cell Sci 125, 795–799. Joubert, P.E., Werneke, S.W., de la Calle, C., Guivel-Benhassine, F., Giodini, A., Peduto, L., et al. (2012). Chikungunya virusinduced autophagy delays caspase-dependent cell death. J Exp Med 209, 1029–1047. Kim, I., Rodriguez-Enriquez, S., and Lemasters, J.J. (2007). Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys 462, 245–253. Kim, S.J., Khan, M., Quan, J., Till, A., Subramani, S., and Siddiqui, A. (2013a). Hepatitis B virus disrupts mitochondrial dynamics: induces fission and mitophagy to attenuate apoptosis. PLoS Pathog 9, e1003722. Kim, S.J., Syed, G.H., and Siddiqui, A. (2013b). Hepatitis C virus induces the mitochondrial translocation of Parkin and subsequent mitophagy. PLoS Pathog 9, e1003285. Kim, S.J., Syed, G.H., Khan, M., Chiu, W.W., Sohail, M.A., Gish, R.G., et al. (2014). Hepatitis C virus triggers mitochondrial fission and attenuates apoptosis to promote viral persistence. Proc Natl Acad Sci U S A 111, 6413–6418. Knodler, L.A., and Celli, J. (2011). Eating the strangers within: host control of intracellular bacteria via xenophagy. Cell Microbiol 13, 1319–1327. Kudchodkar, S.B., and Levine, B. (2009). Viruses and autophagy. Rev Med Virol 19, 359–378. Kyei, G.B., Dinkins, C., Davis, A.S., Roberts, E., Singh, S.B., Dong, C., et al. (2009) Autophagy pathway intersects with HIV-1 biosynthesis and regulates viral yields in macrophages. J Cell Biol 186, 255–268. Lartigue, L., and Faustin, B. (2013). Mitochondria: metabolic regulators of innate immune responses to pathogens and cell stress. Int J Biochem Cell Biol 45, 2052–2056. Levine, B. (2005). Eating oneself and uninvited guests: autophagyrelated pathways in cellular defense. Cell 120, 159–162. Li, W., Yang, Q., and Mao, Z. (2011). Chaperone-mediated autophagy: machinery, regulation and biological consequences. Cell Mol Life Sci 68, 749–763. Lupfer, C., Thomas, P.G., Anand, P.K., Vogel, P., Milasta, S., Martinez, J., et al. (2013). Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection. Nat Immunol 14, 480–488. Lussignol, M., Queval, C., Bernet-Camard, M.F., Cotte-Laffitte, J., Beau, I., Codogno, P., et al. (2013). The herpes simplex virus 1 Us11 protein inhibits autophagy through its interaction with the protein kinase PKR. J Virol 87, 859–871. Maier, H.J., and Britton, P. (2012). Involvement of autophagy in coronavirus replication. Viruses 4, 3440–3451. Maiuri, M.C., Zalckvar, E., Kimchi, A., and Kroemer, G. (2007). Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 8, 741–752. Mathew, R., Karp, C.M., Beaudoin, B., Vuong, N., Chen, G., Chen, H.Y., et al. (2009). Autophagy suppresses tumorigenesis through elimination of p62. Cell 137, 1062–1075.
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McLean, J.E., Wudzinska, A., Datan, E., Quaglino, D., and Zakeri, Z. (2011). Flavivirus NS4A-induced autophagy protects cells against death and enhances virus replication. J Biol Chem 286, 22147–22159. Meiffren, G., Joubert, P.E., Gregoire, I.P., Codogno, P., Rabourdin-Combe, C., and Faure, M. (2010). Pathogen recognition by the cell surface receptor CD46 induces autophagy. Autophagy 6, 299–300. Msaouel, P., Dispenzieri, A., and Galanis, E. (2009). Clinical testing of engineered oncolytic measles virus strains in the treatment of cancer: an overview. Curr Opin Mol Ther 11, 43–53. Richetta, C., Gregoire, I.P., Verlhac, P., Azocar, O., Baguet, J., Flacher, M., et al. (2013). Sustained autophagy contributes to measles virus infectivity. PLoS Pathog 9, e1003599. Rodriguez-Rocha, H., Gomez-Gutierrez, J.G., Garcia-Garcia, A., Rao, X.M., Chen, L., McMasters, K.M., et al. (2011). Adenoviruses induce autophagy to promote virus replication and oncolysis. Virology 416, 9–15. Rossman, J.S., and Lamb, R.A. (2009). Autophagy, apoptosis, and the influenza virus M2 protein. Cell Host Microbe 6, 299–300. Russell, S.J., and Peng, K.W. (2009). Measles virus for cancer therapy. Curr Top Microbiol Immunol 330, 213–241. Russell, S.J., Peng, K.W., and Bell, J.C. (2012). Oncolytic virotherapy. Nat Biotechnol 30, 658–670. Shrivastava, S., Raychoudhuri, A., Steele, R., Ray, R., and Ray, R.B. (2011). Knockdown of autophagy enhances the innate immune response in hepatitis C virus-infected hepatocytes. Hepatology 53, 406–414. Singh, S.B., Ornatowski, W., Vergne, I., Naylor, J., Delgado, M., Roberts, E., et al. (2010). Human IRGM regulates autophagy and cell-autonomous immunity functions through mitochondria. Nat Cell Biol 12, 1154–1165. Taylor, M.P., and Kirkegaard, K. (2007). Modification of cellular autophagy protein LC3 by poliovirus. J Virol 81, 12543– 12553. Thompson, H.G., Harris, J.W., Wold, B.J., Lin, F., and Brody, J.P. (2003). p62 overexpression in breast tumors and regulation by prostate-derived Ets factor in breast cancer cells. Oncogene 22, 2322–2333. West, A.P., Shadel, G.S., and Ghosh, S. (2011). Mitochondria in innate immune responses. Nat Rev Immunol 11, 389–402.
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Wild, P., Farhan, H., McEwan, D.G., Wagner, S., Rogov, V.V., Brady, N.R., et al. (2011). Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333, 228–233. Xia, M., Gonzalez, P., Li, C., Meng, G., Jiang, A., Wang, H., et al. (2014a). Mitophagy enhances oncolytic measles virus replication by mitigating DDX58/RIG-I-like receptor signaling. J Virol 88, 5152–5164. Xia, M., Meng, G., Jiang, A., Chen, A., Dahlhaus, M., Gonzalez, P., et al. (2014b). Mitophagy switches cell death from apoptosis to necrosis in NSCLC cells treated with oncolytic measles virus. Oncotarget 5, 3907–3918. Yang, Y., Xing, D., Zhou, F., and Chen, Q. (2010). Mitochondrial autophagy protects against heat shock-induced apoptosis through reducing cytosolic cytochrome c release and downstream caspase-3 activation. Biochem Biophys Res Commun 395, 190–195. Zhang, J., and Ney, PA. (2009). Role of BNIP3 and NIX in cell death, autophagy, and mitophagy. Cell Death Differ 16, 939– 946. Zhu, Y., Massen, S., Terenzio, M., Lang, V., Chen-Lindner, S., Eils, R., et al. (2013). Modulation of serines 17 and 24 in the LC3-interacting region of Bnip3 determines pro-survival mitophagy versus apoptosis. J Biol Chem 288, 1099– 1113.
Address correspondence to: Jiwu Wei, MD Jiangsu Key Laboratory of Molecular Medicine Medical School The State Key Laboratory of Pharmaceutical Biotechnology Nanjing University 22 Hankou Road 210093 Nanjing China E-mail: [email protected] Received for publication June 21, 2014; accepted June 21, 2014.
DNACB BITS
Mitophagy in Viral Infections Mao Xia, Gang Meng, Min Li, and Jiwu Wei
Antiviral innate immune responses and apoptosis are the two major factors limiting viral infections. Successful viral infection requires the virus to take advantage of the cellular machinery to bypass cellular defenses. Accumulated evidences show that autophagy plays a crucial role in cell-to-virus interaction. Here, we focus on how viruses subvert mitophagy to favor viral replication by mitigating innate immune responses and apoptotic signaling.
Autophagy and Viral Infections
A
utophagy is a highly conserved homeostatic process, which allows cells to recycle their components and to remove dysfunctional organelles. A hallmark in this process is the formation of the double-membrane vesicles packing components targeted for lysosomal degradation (Deretic and Levine, 2009; Zhang and Ney, 2009; Geisler et al., 2010). There are at least three different patterns of autophagy, including microautophagy, chaperone-mediated autophagy, and macroautophagy (Crotzer and Blum, 2010; Li et al., 2011). Autophagy and/or autophagy-related proteins can be both proviral and antiviral factors depending on viral subtypes (Kudchodkar and Levine, 2009). Recent works show that autophagy is involved in the regulation of inflammation and constitutes an essential innate responsive mechanism defending pathogens in primitive eukaryotic cells (Kudchodkar and Levine, 2009; Deretic, 2012). Autophagy can engulf bacteria and viruses for lysosomal degradation (Levine, 2005; Knodler and Celli, 2011; Wild et al., 2011). Moreover, autophagy is also required for presenting viral antigens to major histocompatibility complex class II, leading to the activation of adaptive immunity (Hayward and Dinesh-Kumar, 2010). Interestingly, some viruses have evolved countermeasures to escape the antiviral properties of autophagy. For instance, matrix protein 2 of influenza A virus and Nef protein of human immunodeficiency virus inhibit the maturation of autophagosomes into autolysosomes by targeting beclin1 (Gannage et al., 2009; Kyei et al., 2009; Rossman and Lamb, 2009). Herpes simplex virus 1 restrains early stage of autophagic process through its Us 11 protein interacting with the protein kinase PKR (Lussignol et al., 2013). In contrast, some viruses can benefit from autophagy for their infections. Several families of RNA viruses may subvert autophagy for their replication by targeting immunityassociated GTPase family M (IRGM) (Gregoire et al., 2011). In addition, some viruses utilize autophagic mechanisms for enhanced viral transmission and replication to be even more
devastating, such as dengue virus (Heaton and Randall, 2011), hepatitis C virus (Shrivastava et al., 2011), poliovirus (Taylor and Kirkegaard, 2007), coronaviruses (Maier and Britton, 2012), chikungunya virus ( Joubert et al., 2012), and adenovirus (Rodriguez-Rocha et al., 2011). Mitophagy Promotes Viral Replication by Mitigating Antiviral Immune Responses
Mitophagy is known as a process of the selective engulfment of mitochondria by autophagosomes and their subsequent degradation by lysosomes (Kim et al., 2007), which functions as selective removal of damaged mitochondria ( Jin and Youle, 2012). Mitophagy occurs after recognition of altered mitochondria by some autophagic receptors, such as SQSTM1, ATG32, or NIX (Zhang and Ney, 2009; Geisler et al., 2010; Aoki et al., 2011). The crucial role of mitophagy in manipulation of viral infections is now getting clarified. Previous studies have observed mitophagy in cells infected by seasonal influenza A virus (Lupfer et al., 2013), hepatitis C virus (Kim et al., 2013b, 2014), and hepatitis B virus (Kim et al., 2013a). Following seasonal influenza A virus infection, receptor interacting protein kinase 2 (RIPK2)-mediated mitophagy reduces immunopathology by negatively regulating activation of NOD-like receptor family pyrin-containing domain protein 3 (NLRP3) signaling and inflammation (Lupfer et al., 2013). We have recently reported that measles virus Edmonston vaccine strain (MV-Edm) infection induces mitophagy in nonsmall cell lung cancer (NSCLC) cells leading to enhanced viral replication (Xia et al., 2014a). While MV-Edm infection induces innate immune responses by means of activation of DDX58/MAVS, it in parallel stimulates SQSTM1mediated mitophagy to degrade mitochondrion-tethered mitochondrial antiviral signaling protein (MAVS), a key adaptor protein of DDX58/IFIH1 signaling, and thus attenuates antiviral immune responses (Fig. 1). In this process, SQSTM1 plays a critical role in tipping the balance of antiviral or proviral roles of autophagy following MV-Edm
Jiangsu Key Laboratory of Molecular Medicine, Medical School, The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
739
740
FIG. 1. Measles virus Edmonston vaccine strain (MV-Edm) subverts mitophagy to attenuate both innate immune responses and apoptosis. In this model, antiviral innate immunity and apoptosis are countermeasures limiting MV-Edm infections (antiviral path). MV-Edm subverts mitophagy to bypass these restrictions by two different mechanisms: mitophagy-mediated reduction of mitochondrion-tethered mitochondrial antiviral signaling protein (MAVS) and mitophagy-mediated reduction of cytochromecrelease (proviralpath).SQSTM1mayplaya crucial role in tipping the balance of antiviral or proviral functions of autophagy enhancing replication of MV-Edm, as it mediates mitophagy. infection. Of note, many previous studies show that SQSTM1 is upregulated in many cancers (Thompson et al., 2003; Duran et al., 2008; Mathew et al., 2009), which might explain why oncolytic viruses preferentially replicate in cancers. The induction of mitophagy by MV-Edm remains to be determined. It is possible that MV-Edm causes mitochondrial dysfunction by not yet well-defined mechanisms, thereby targeting mitochondria toward autophagic degradation. Mitochondrial dynamics also regulate antiviral innate immune responses. Mitochondrial fusion may increase the interaction of key factors such as MAVS in signaling of immune responses, and mitochondrial fission may mitigate these pathways (Castanier et al., 2010; West et al., 2011; Lartigue and Faustin, 2013). Given that IRGM contributes to proviral autophagy following measles virus infection (Gregoire et al., 2011) and that IRGM is implicated in the regulation of mitochondrial fission (Singh et al., 2010), it remains to be clarified whether IRGM primes infected cells for mitophagy by disrupting mitochondria dynamics. Mitophagy Favors Viral Replication by Attenuation of Apoptosis
Apoptosis is another crucial mechanism by which hosts defend themselves against viral infection. Since self-destruction may restrict viral replication and spread. However, viruses evolve various mechanisms to delay or prevent apoptosis.
XIA ET AL.
Recent studies unveil various cross talks between autophagy and apoptosis. It has been shown that autophagy inhibits apoptosis by preventing the activation of Bid or degrading active caspase-8 by Beclin 1 (Djavaheri-Mergny et al., 2010). Cleaved ATG5 by calpains translocates to mitochondria and interacts Bcl-xL leading to controlled cytochrome c release (Giansanti et al., 2011). Bcl-2 or Bcl-xL inhibits the proautophagic activity of Beclin 1 by binding to Beclin 1 (Maiuri et al., 2007). In line with these, autophagy can be utilized by viruses to counteract apoptosis. For instance, autophagy induced by chikungunya virus delays caspase-dependent cell death by the IRE1a–XBP-1 pathway interaction with ROSmediated mTOR inhibition ( Joubert et al., 2012), and autophagy induced by flavivirus NS4A protein protects epithelial cells from cell death (McLean et al., 2011). As mitochondria are regarded to function as the central executioner in apoptotic pathways (Estaquier et al., 2012), it is plausible that mitophagy may participate in the modulation of apoptosis. Indeed, Bnip3-induced mitophagy negatively regulates cytochrome c release capacity by mitophagic degradation of mitochondria before dysfunction (i.e., mitochondrial membrane permeability transition, depolarization, and release of cytochrome c), which results in decreased apoptosis (Zhu et al., 2013). Another study shows that mitophagy eliminates damaged mitochondria and thus reduces cytochrome c release to cytoplasm under heat shock (Yang et al., 2010). Recent studies also unveil the role of mitophagy in controlling apoptosis following viral infections. We find that mitophagy induced by MV-Edm switches cell death from apoptosis to necrosis in NSCLCs (Xia et al., 2014b). In addition to attenuation of antiviral immunity, mitophagy is also utilized by MV-Edm to eliminate defective mitochondria before cytochrome c is released, which results in decreased apoptosis following viral infection and therefore sustains viral replication in NSCLCs (Fig. 1). Several other studies show that HBV and HCV induce Drp1-mediated mitochondrial fission (mitochondrial fragmentation) and Parkin-dependent mitophagy, which attenuate apoptosis by reducing cytochrome c release and may have significant contribution in persisting viral infection (Kim et al., 2013a, 2013b, 2014). An Introduction of Measles Virus Edmonston Vaccine Strain
Measles virus is a negative-sense single-strand RNA paramyxovirus. The attenuated strains of the Edmonston vaccine lineage (MV-Edm) have been used for vaccination over 50 years with excellent safety records (Blechacz et al., 2006). In the past decades, MV-Edm and its genetic engineered substrains has been proved as promising oncolytic viruses against a number of tumor types, including ovarian cancer, glioma, myeloma, mesothelioma, adult brain tumor, and lymphoma (Russell et al., 2012). As an excellent oncolytic virus with safety records, MV-Edm has been investigated in several clinical trials and holds promising for advanced cancer patients (Russell and Peng, 2009; Russell et al., 2012). MVEdm enters cells via its cognate membrane-bound receptor CD46, which has been shown overexpressed on tumor cells (Msaouel et al., 2009). It has also been shown that measles virus could promote proviral autophagy by means of IRGMdependent pathway (Gregoire et al., 2011). Autophagosomal formation can be triggered by MV-Edm at very early stage
MITOPHAGY IN VIRAL INFECTIONS
during infection through a CD46-Cyt-1/GOPC pathway and matures into autolysosomes (Meiffren et al., 2010). At the late stage following infection, MV-Edm protein C contributes to sustain autophagy for viral infectivity (Richetta et al., 2013). Perspectives
Mitophagy favors measles virus replication by two different ways: mitophagy-mediated reduction of mitochondriontethered MAVS and mitophagy-mediated reduction of cytochrome c release. It deserves further intensive investigations to clarify if such mechanisms are also commonly subverted by other viruses. This will be of great interest not only for designing antiviral strategies but also for oncolytic virotherapies. Acknowledgments
This work was supported by the National Natural Science Foundation of China (81071860 and 81172143), Jiangsu Special Program for Clinical Medical Science and Technology (BL2014054), and the State Key Laboratory of Pharmaceutical Biotechnology (KF-GN-201301). Disclosure Statement
The authors have no conflicts of interest. References
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Address correspondence to: Jiwu Wei, MD Jiangsu Key Laboratory of Molecular Medicine Medical School The State Key Laboratory of Pharmaceutical Biotechnology Nanjing University 22 Hankou Road 210093 Nanjing China E-mail: [email protected] Received for publication June 21, 2014; accepted June 21, 2014.
