Abstract
Autophagy is a catabolic process by which cells remove protein aggregates and damaged organelles for recycling. It can also be used by cells to remove intracellular microbial pathogens, including viruses, in a process known as xenophagy. However, many viruses have developed mechanisms to subvert this intracellular antiviral response and even use this pathway to support their own replications. Hepatitis C virus (HCV) is one such virus and is an important human pathogen that can cause severe liver diseases. Recent studies indicated that HCV could activate the autophagic pathway to support its replication. This review summarizes the current knowledge on the interplay between HCV and autophagy and how this interplay affects HCV replication and host innate immune responses.
Acknowledgments
This work is supported by National Institutes of Diabetes and Digestive and Kidney Diseases grants DK094652, DK100257 and National Cancer Institute CA177337.
References
Ait-Goughoulte, M., Kanda, T., Meyer, K., Ryerse, J.S., Ray, R.B., and Ray, R. (2008). Hepatitis C virus genotype 1a growth and induction of autophagy. J. Virol. 82, 2241–2249.10.1128/JVI.02093-07Search in Google Scholar PubMed PubMed Central
Aweya, J.J., Mak, T.M., Lim, S.G., and Tan, Y.J. (2013). The p7 protein of the hepatitis C virus induces cell death differently from the influenza A virus viroporin M2. Virus Res. 172, 24–34.10.1016/j.virusres.2012.12.005Search in Google Scholar PubMed PubMed Central
Bartenschlager, R. and Lohmann, V. (2000). Replication of hepatitis C virus. J. Gen. Virol. 81, 1631–1648.10.1053/bega.1999.0073Search in Google Scholar
Chatterji, U., Bobardt, M., Tai, A., Wood, M., and Gallay, P.A. (2015). Cyclophilin and NS5A inhibitors, but not other anti-hepatitis C virus (HCV) agents, preclude HCV-mediated formation of double-membrane-vesicle viral factories. Antimicrob. Agents Chemother. 59, 2496–2507.10.1128/AAC.04958-14Search in Google Scholar PubMed PubMed Central
Desai, M.M., Gong, B., Chan, T., Davey, R.A., Soong, L., Kolokoltsov, A.A., and Sun, J. (2011). Differential, type I interferon-mediated autophagic trafficking of hepatitis C virus proteins in mouse liver. Gastroenterology 141, 674–685, 685 e671–e676.10.1053/j.gastro.2011.04.060Search in Google Scholar PubMed PubMed Central
Dreux, M., Gastaminza, P., Wieland, S.F., and Chisari, F.V. (2009). The autophagy machinery is required to initiate hepatitis C virus replication. Proc. Natl. Acad. Sci. USA 106, 14046–14051.10.1073/pnas.0907344106Search in Google Scholar PubMed PubMed Central
Ferraris, P., Blanchard, E., and Roingeard, P. (2010). Ultrastructural and biochemical analyses of hepatitis C virus-associated host cell membranes. J. Gen. Virol. 91, 2230–2237.10.1099/vir.0.022186-0Search in Google Scholar PubMed
Foy, E., Li, K., Sumpter, R., Jr., Loo, Y.M., Johnson, C.L., Wang, C., Fish, P.M., Yoneyama, M., Fujita, T., Lemon, S.M., et al. (2005). Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling. Proc. Natl. Acad. Sci. USA 102, 2986–2991.10.1073/pnas.0408707102Search in Google Scholar PubMed PubMed Central
Gomes, L.C. and Dikic, I. (2014). Autophagy in antimicrobial immunity. Mol. Cell 54, 224–233.10.1016/j.molcel.2014.03.009Search in Google Scholar PubMed
Gregoire, I.P., Richetta, C., Meyniel-Schicklin, L., Borel, S., Pradezynski, F., Diaz, O., Deloire, A., Azocar, O., Baguet, J., Le Breton, M., et al. (2011). IRGM is a common target of RNA viruses that subvert the autophagy network. PLoS Pathog. 7, e1002422.10.1371/journal.ppat.1002422Search in Google Scholar PubMed PubMed Central
Guevin, C., Manna, D., Belanger, C., Konan, K.V., Mak, P., and Labonte, P. (2010). Autophagy protein ATG5 interacts transiently with the hepatitis C virus RNA polymerase (NS5B) early during infection. Virology 405, 1–7.10.1016/j.virol.2010.05.032Search in Google Scholar PubMed PubMed Central
Hetz, C. (2012). The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat. Rev. Mol. Cell. Biol. 13, 89–102.10.1038/nrm3270Search in Google Scholar PubMed
Huang, H., Kang, R., Wang, J., Luo, G., Yang, W., and Zhao, Z. (2013). Hepatitis C virus inhibits AKT-tuberous sclerosis complex (TSC), the mechanistic target of rapamycin (MTOR) pathway, through endoplasmic reticulum stress to induce autophagy. Autophagy 9, 175–195.10.4161/auto.22791Search in Google Scholar PubMed PubMed Central
Jounai, N., Takeshita, F., Kobiyama, K., Sawano, A., Miyawaki, A., Xin, K.Q., Ishii, K.J., Kawai, T., Akira, S., Suzuki, K., et al. (2007). The Atg5 Atg12 conjugate associates with innate antiviral immune responses. Proc. Natl. Acad. Sci. USA 104, 14050–14055.10.1073/pnas.0704014104Search in Google Scholar PubMed PubMed Central
Joyce, M.A., Walters, K.A., Lamb, S.E., Yeh, M.M., Zhu, L.F., Kneteman, N., Doyle, J.S., Katze, M.G., and Tyrrell, D.L. (2009). HCV induces oxidative and ER stress, and sensitizes infected cells to apoptosis in SCID/Alb-uPA mice. PLoS Pathog. 5, e1000291.10.1371/journal.ppat.1000291Search in Google Scholar PubMed PubMed Central
Ke, P.Y. and Chen, S.S. (2011). Activation of the unfolded protein response and autophagy after hepatitis C virus infection suppresses innate antiviral immunity in vitro. J. Clin. Invest. 121, 37–56.10.1172/JCI41474Search in Google Scholar PubMed PubMed Central
Kim, S.J., Syed, G.H., and Siddiqui, A. (2013). Hepatitis C virus induces the mitochondrial translocation of Parkin and subsequent mitophagy. PLoS Pathog. 9, e1003285.10.1371/journal.ppat.1003285Search in Google Scholar PubMed PubMed Central
Kim, S.J., Syed, G.H., Khan, M., Chiu, W.W., Sohail, M.A., Gish, R.G., and Siddiqui, A. (2014). Hepatitis C virus triggers mitochondrial fission and attenuates apoptosis to promote viral persistence. Proc. Natl. Acad. Sci. USA 111, 6413–6418.10.1073/pnas.1321114111Search in Google Scholar PubMed PubMed Central
Levine, B. and Kroemer, G. (2008). Autophagy in the pathogenesis of disease. Cell 132, 27–42.10.1016/j.cell.2007.12.018Search in Google Scholar PubMed PubMed Central
Li, X.D., Sun, L., Seth, R.B., Pineda, G., and Chen, Z.J. (2005). Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc. Natl. Acad. Sci. USA 102, 17717–17722.10.1073/pnas.0508531102Search in Google Scholar PubMed PubMed Central
Li, S., Ye, L., Yu, X., Xu, B., Li, K., Zhu, X., Liu, H., Wu, X., and Kong, L. (2009). Hepatitis C virus NS4B induces unfolded protein response and endoplasmic reticulum overload response-dependent NF-κB activation. Virology 391, 257–264.10.1016/j.virol.2009.06.039Search in Google Scholar PubMed
Li, X.D., Chiu, Y.H., Ismail, A.S., Behrendt, C.L., Wight-Carter, M., Hooper, L.V., and Chen, Z.J. (2011). Mitochondrial antiviral signaling protein (MAVS) monitors commensal bacteria and induces an immune response that prevents experimental colitis. Proc. Natl. Acad. Sci. USA 108, 17390–17395.10.1073/pnas.1107114108Search in Google Scholar PubMed PubMed Central
Liang, C., Lee, J.S., Inn, K.S., Gack, M.U., Li, Q., Roberts, E.A., Vergne, I., Deretic, V., Feng, P., Akazawa, C., et al. (2008). Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking. Nat. Cell Biol. 10, 776–87.10.1038/ncb1740Search in Google Scholar PubMed PubMed Central
Matsunaga, K., Saitoh, T., Tabata, K., Omori, H., Satoh, T., Kurotori, N., Maejima, I., Shirahama-Noda, K., Ichimura, T., Isobe, T., et al. (2009). Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat. Cell Biol. 11, 385–396.10.1038/ncb1846Search in Google Scholar PubMed
Mizui, T., Yamashina, S., Tanida, I., Takei, Y., Ueno, T., Sakamoto, N., Ikejima, K., Kitamura, T., Enomoto, N., Sakai, T., et al. (2010). Inhibition of hepatitis C virus replication by chloroquine targeting virus-associated autophagy. J. Gastroenterol. 45, 195–203.10.1007/s00535-009-0132-9Search in Google Scholar PubMed PubMed Central
Mohl, B.P., Tedbury, P.R., Griffin, S., and Harris, M. (2012). Hepatitis C virus-induced autophagy is independent of the unfolded protein response. J. Virol. 86, 10724–10732.10.1128/JVI.01667-12Search in Google Scholar PubMed PubMed Central
Moradpour, D., Penin, F., and Rice, C.M. (2007). Replication of hepatitis C virus. Nat. Rev. Microbiol. 5, 453–463.10.1038/nrmicro1645Search in Google Scholar PubMed
Paul, D., Hoppe, S., Saher, G., Krijnse-Locker, J., and Bartenschlager, R. (2013). Morphological and biochemical characterization of the membranous hepatitis C virus replication compartment. J. Virol. 87, 10612–10627.10.1128/JVI.01370-13Search in Google Scholar PubMed PubMed Central
Quan, M., Liu, S., Li, G., Wang, Q., Zhang, J., Zhang, M., Li, M., Gao, P., Feng, S., and Cheng, J. (2014). A functional role for NS5ATP9 in the induction of HCV NS5A-mediated autophagy. J. Viral Hepat. 21, 405–415.10.1111/jvh.12155Search in Google Scholar PubMed
Rautou, P.E., Cazals-Hatem, D., Feldmann, G., Mansouri, A., Grodet, A., Barge, S., Martinot-Peignoux, M., Duces, A., Bieche, I., Lebrec, D., et al. (2011). Changes in autophagic response in patients with chronic hepatitis C virus infection. Am. J. Pathol. 178, 2708–2715.10.1016/j.ajpath.2011.02.021Search in Google Scholar PubMed PubMed Central
Romero-Brey, I., Merz, A., Chiramel, A., Lee, J.Y., Chlanda, P., Haselman, U., Santarella-Mellwig, R., Habermann, A., Hoppe, S., Kallis, S., et al. (2012). Three-dimensional architecture and biogenesis of membrane structures associated with hepatitis C virus replication. PLoS Pathog. 8, e1003056.10.1371/journal.ppat.1003056Search in Google Scholar PubMed PubMed Central
Shepard, C.W., Finelli, L., and Alter, M.J. (2005). Global epidemiology of hepatitis C virus infection. Lancet Infect. Dis. 5, 558–567.10.1016/S1473-3099(05)70216-4Search in Google Scholar
Shinohara, Y., Imajo, K., Yoneda, M., Tomeno, W., Ogawa, Y., Kirikoshi, H., Funakoshi, K., Ikeda, M., Kato, N., Nakajima, A., et al. (2013). Unfolded protein response pathways regulate Hepatitis C virus replication via modulation of autophagy. Biochem. Biophys. Res. Commun. 432, 326–332.10.1016/j.bbrc.2013.01.103Search in Google Scholar PubMed PubMed Central
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, 406–414.10.1002/hep.24073Search in Google Scholar PubMed PubMed Central
Shrivastava, S., Bhanja Chowdhury, J., Steele, R., Ray, R., and Ray, R.B. (2012). Hepatitis C virus upregulates Beclin1 for induction of autophagy and activates mTOR signaling. J. Virol. 86, 8705–8712.10.1128/JVI.00616-12Search in Google Scholar PubMed PubMed Central
Simonsen, A. and Tooze, S.A. (2009). Coordination of membrane events during autophagy by multiple class III PI3-kinase complexes. J. Cell Biol. 186, 773–782.10.1083/jcb.200907014Search in Google Scholar PubMed PubMed Central
Sir, D., Chen, W.L., Choi, J., Wakita, T., Yen, T.S., and Ou, J.H. (2008). Induction of incomplete autophagic response by hepatitis C virus via the unfolded protein response. Hepatology 48, 1054–1061.10.1002/hep.22464Search in Google Scholar PubMed PubMed Central
Sir, D., Kuo, C.F., Tian, Y., Liu, H.M., Huang, E.J., Jung, J.U., Machida, K., and Ou, J.H. (2012). Replication of hepatitis C virus RNA on autophagosomal membranes. J. Biol. Chem. 287, 18036–18043.10.1074/jbc.M111.320085Search in Google Scholar PubMed PubMed Central
Stone, M., Jia, S., Heo, W.D., Meyer, T., and Konan, K.V. (2007). Participation of rab5, an early endosome protein, in hepatitis C virus RNA replication machinery. J. Virol. 81, 4551–4563.10.1128/JVI.01366-06Search in Google Scholar PubMed PubMed Central
Su, W.C., Chao, T.C., Huang, Y.L., Weng, S.C., Jeng, K.S., and Lai, M.M. (2011). Rab5 and class III phosphoinositide 3-kinase Vps34 are involved in hepatitis C virus NS4B-induced autophagy. J. Virol. 85, 10561–10571.10.1128/JVI.00173-11Search in Google Scholar PubMed PubMed Central
Sun, Q., Westphal, W., Wong, K.N., Tan, I., and Zhong, Q. (2010). Rubicon controls endosome maturation as a Rab7 effector. Proc. Natl. Acad. Sci. USA 107, 19338–19343.10.1073/pnas.1010554107Search in Google Scholar PubMed PubMed Central
Taguwa, S., Kambara, H., Fujita, N., Noda, T., Yoshimori, T., Koike, K., Moriishi, K., and Matsuura, Y. (2011). Dysfunction of autophagy participates in vacuole formation and cell death in cells replicating hepatitis C virus. J. Virol. 85, 13185–13194.10.1128/JVI.06099-11Search in Google Scholar PubMed PubMed Central
Tanida, I., Fukasawa, M., Ueno, T., Kominami, E., Wakita, T., and Hanada, K. (2009). Knockdown of autophagy-related gene decreases the production of infectious hepatitis C virus particles. Autophagy 5, 937–945.10.4161/auto.5.7.9243Search in Google Scholar PubMed
Tardif, K.D., Mori, K., and Siddiqui, A. (2002). Hepatitis C virus subgenomic replicons induce endoplasmic reticulum stress activating an intracellular signaling pathway. J. Virol. 76, 7453–7459.10.1128/JVI.76.15.7453-7459.2002Search in Google Scholar PubMed PubMed Central
Tardif, K.D., Waris, G., and Siddiqui, A. (2005). Hepatitis C virus, ER stress, and oxidative stress. Trends Microbiol. 13, 159–163.10.1016/j.tim.2005.02.004Search in Google Scholar PubMed
Tellinghuisen, T.L., Evans, M.J., von Hahn, T., You, S., and Rice, C.M. (2007). Studying hepatitis C virus: making the best of a bad virus. J. Virol. 81, 8853–8867.10.1128/JVI.00753-07Search in Google Scholar PubMed PubMed Central
Vescovo, T., Romagnoli, A., Perdomo, A.B., Corazzari, M., Ciccosanti, F., Alonzi, T., Nardacci, R., Ippolito, G., Tripodi, M., Garcia-Monzon, C., et al. (2012). Autophagy protects cells from HCV-induced defects in lipid metabolism. Gastroenterology 142, 644–653, e643.10.1053/j.gastro.2011.11.033Search in Google Scholar PubMed
Wang, M. and Kaufman, R.J. (2014). The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nat. Rev. Cancer 14, 581–597.10.1038/nrc3800Search in Google Scholar PubMed
Wang, J., Kang, R., Huang, H., Xi, X., Wang, B., Wang, J., and Zhao, Z. (2014). Hepatitis C virus core protein activates autophagy through EIF2AK3 and ATF6 UPR pathway- mediated MAP1LC3B and ATG12 expression. Autophagy 10, 766–784.10.4161/auto.27954Search in Google Scholar PubMed PubMed Central
Wang, L., Tian, Y., and Ou, J.H. (2015). HCV induces the expression of Rubicon and UVRAG to temporally regulate the maturation of autophagosomes and viral replication. PLoS Pathog. 11, e1004764.10.1371/journal.ppat.1004764Search in Google Scholar PubMed PubMed Central
Youle, R.J. and Narendra, D.P. (2011). Mechanisms of mitophagy. Nat. Rev. Mol. Cell. Biol. 12, 9–14.10.1038/nrm3028Search in Google Scholar PubMed PubMed Central
Zheng, Y., Gao, B., Ye, L., Kong, L., Jing, W., Yang, X., Wu, Z., and Ye, L. (2005). Hepatitis C virus non-structural protein NS4B can modulate an unfolded protein response. J. Microbiol. 43, 529–536.Search in Google Scholar
©2015 by De Gruyter
