Acknowledgement
This work was supported by grant from the Korea National Institute of Health (2014-NG51001 and 2016-NG51005 for S.M.K.). This work was also supported by the NRF grant funded by the Korea government (MSIT) (2021R1A2C2003275 for S.B.H.).
References
- Adli, M. and Baldwin, A.S. (2006). IKK-i/IKKepsilon controls constitutive, cancer cell-associated NF-kappaB activity via regulation of Ser-536 p65/ RelA phosphorylation. J. Biol. Chem. 281, 26976-26984. https://doi.org/10.1074/jbc.M603133200
- Appel, N., Pietschmann, T., and Bartenschlager, R. (2005). Mutational analysis of hepatitis C virus nonstructural protein 5A: potential role of differential phosphorylation in RNA replication and identification of a genetically flexible domain. J. Virol. 79, 3187-3194. https://doi.org/10.1128/JVI.79.5.3187-3194.2005
- Appel, N., Zayas, M., Miller, S., Krijnse-Locker, J., Schaller, T., Friebe, P., Kallis, S., Engel, U., and Bartenschlager, R. (2008). Essential role of domain III of nonstructural protein 5A for hepatitis C virus infectious particle assembly. PLoS Pathog. 4, e1000035. https://doi.org/10.1371/journal.ppat.1000035
- Asabe, S.I., Tanji, Y., Satoh, S., Kaneko, T., Kimura, K., and Shimotohno, K. (1997). The N-terminal region of hepatitis C virus-encoded NS5A is important for NS4A-dependent phosphorylation. J. Virol. 71, 790-796. https://doi.org/10.1128/jvi.71.1.790-796.1997
- Balka, K.R., Louis, C., Saunders, T.L., Smith, A.M., Calleja, D.J., D'Silva, D.B., Moghaddas, F., Tailler, M., Lawlor, K.E., Zhan, Y., et al. (2020). TBK1 and IKKε act redundantly to mediate STING-induced NF-κB responses in myeloid cells. Cell Rep. 31, 107492. https://doi.org/10.1016/j.celrep.2020.03.056
- Brownell, J., Bruckner, J., Wagoner, J., Thomas, E., Loo, Y.M., Gale, M., Jr., Liang, T.J., and Polyak, S.J. (2014). Direct, interferon-independent activation of the CXCL10 promoter by NF-kappaB and interferon regulatory factor 3 during hepatitis C virus infection. J. Virol. 88, 1582-1590. https://doi.org/10.1128/JVI.02007-13
- Choi, J.W., Kim, J.W., Nguyen, L.P., Nguyen, H.C., Park, E.M., Choi, D.H., Han, K.M., Kang, S.M., Tark, D., Lim, Y.S., et al. (2020). Nonstructural NS5A protein regulates LIM and SH3 domain protein 1 to promote hepatitis C virus propagation. Mol. Cells 43, 469-478.
- Choi, S.H. and Hwang, S.B. (2006). Modulation of TGF-beta signal transduction pathway by hepatitis C virus nonstructural 5A protein. J. Biol. Chem. 281, 7468-7478. https://doi.org/10.1074/jbc.M512438200
- Ferreon, J.C., Ferreon, A.C., Li, K., and Lemon, S.M. (2005). Molecular determinants of TRIF proteolysis mediated by the hepatitis C virus NS3/4A protease. J. Biol. Chem. 280, 20483-20492. https://doi.org/10.1074/jbc.M500422200
- Fitzgerald, K.A., McWhirter, S.M., Faia, K.L., Rowe, D.C., Latz, E., Golenbock, D.T., Coyle, A.J., Liao, S.M., and Maniatis, T. (2003). IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat. Immunol. 4, 491-496.
- Gale, M., Jr., Blakely, C.M., Kwieciszewski, B., Tan, S.L., Dossett, M., Tang, N.M., Korth, M.J., Polyak, S.J., Gretch, D.R., and Katze, M.G. (1998). Control of PKR protein kinase by hepatitis C virus nonstructural 5A protein: molecular mechanisms of kinase regulation. Mol. Cell. Biol. 18, 5208-5218. https://doi.org/10.1128/MCB.18.9.5208
- Gale, M.J., Jr., Korth, M.J., Tang, N.M., Tan, S.L., Hopkins, D.A., Dever, T.E., Polyak, S.J., Gretch, D.R., and Katze, M.G. (1997). Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein. Virology 230, 217-227. https://doi.org/10.1006/viro.1997.8493
- Gu, L., Fullam, A., Brennan, R., and Schroder, M. (2013). Human DEAD box helicase 3 couples IkappaB kinase epsilon to interferon regulatory factor 3 activation. Mol. Cell. Biol. 33, 2004-2015. https://doi.org/10.1128/MCB.01603-12
- Hoofnagle, J.H. (2002). Course and outcome of hepatitis C. Hepatology 36(5 Suppl 1), S21-S29.
- Indukuri, H., Castro, S.M., Liao, S.M., Feeney, L.A., Dorsch, M., Coyle, A.J., Garofalo, R.P., Brasier, A.R., and Casola, A. (2006). Ikkepsilon regulates viral-induced interferon regulatory factor-3 activation via a redox-sensitive pathway. Virology 353, 155-165. https://doi.org/10.1016/j.virol.2006.05.022
- Jensen, S. and Thomsen, A.R. (2012). Sensing of RNA viruses: a review of innate immune receptors involved in recognizing RNA virus invasion. J. Virol. 86, 2900-2910. https://doi.org/10.1128/JVI.05738-11
- Kanda, T., Steele, R., Ray, R., and Ray, R.B. (2007). Hepatitis C virus infection induces the beta interferon signaling pathway in immortalized human hepatocytes. J. Virol. 81, 12375-12381. https://doi.org/10.1128/JVI.01695-07
- Kaneko, T., Tanji, Y., Satoh, S., Hijikata, M., Asabe, S., Kimura, K., and Shimotohno, K. (1994). Production of two phosphoproteins from the NS5A region of the hepatitis C viral genome. Biochem. Biophys. Res. Commun. 205, 320-326. https://doi.org/10.1006/bbrc.1994.2667
- Kawai, T. and Akira, S. (2006). Innate immune recognition of viral infection. Nat. Immunol. 7, 131-137. https://doi.org/10.1038/ni1303
- Kawai, T. and Akira, S. (2008). Toll-like receptor and RIG-I-like receptor signaling. Ann. N. Y. Acad. Sci. 1143, 1-20. https://doi.org/10.1196/annals.1443.020
- Kawai, T., Takahashi, K., Sato, S., Coban, C., Kumar, H., Kato, H., Ishii, K.J., Takeuchi, O., and Akira, S. (2005). IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat. Immunol. 6, 981-988. https://doi.org/10.1038/ni1243
- Kumthip, K., Chusri, P., Jilg, N., Zhao, L., Fusco, D.N., Zhao, H., Goto, K., Cheng, D., Schaefer, E.A., Zhang, L., et al. (2012). Hepatitis C virus NS5A disrupts STAT1 phosphorylation and suppresses type I interferon signaling. J. Virol. 86, 8581-8591. https://doi.org/10.1128/JVI.00533-12
- Lan, K.H., Lan, K.L., Lee, W.P., Sheu, M.L., Chen, M.Y., Lee, Y.L., Yen, S.H., Chang, F.Y., and Lee, S.D. (2007). HCV NS5A inhibits interferon-alpha signaling through suppression of STAT1 phosphorylation in hepatocytederived cell lines. J. Hepatol. 46, 759-767.
- Lau, D.T., Fish, P.M., Sinha, M., Owen, D.M., Lemon, S.M., and Gale, M., Jr. (2008). Interferon regulatory factor-3 activation, hepatic interferonstimulated gene expression, and immune cell infiltration in hepatitis C virus patients. Hepatology 47, 799-809. https://doi.org/10.1002/hep.22076
- Li, K., Foy, E., Ferreon, J.C., Nakamura, M., Ferreon, A.C., Ikeda, M., Ray, S.C., Gale, M., Jr., and Lemon, S.M. (2005a). Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proc. Natl. Acad. Sci. U. S. A. 102, 2992-2997. https://doi.org/10.1073/pnas.0408824102
- Li, Q., Brass, A.L., Ng, A., Hu, Z., Xavier, R.J., Liang, T.J., and Elledge, S.J. (2009). A genome-wide genetic screen for host factors required for hepatitis C virus propagation. Proc. Natl. Acad. Sci. U. S. A. 106, 16410-16415. https://doi.org/10.1073/pnas.0907439106
- Li, S., Wang, L., Berman, M., Kong, Y.Y., and Dorf, M.E. (2011). Mapping a dynamic innate immunity protein interaction network regulating type I interferon production. Immunity 35, 426-440. https://doi.org/10.1016/j.immuni.2011.06.014
- Li, X.D., Sun, L., Seth, R.B., Pineda, G., and Chen, Z.J. (2005b). Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc. Natl. Acad. Sci. U. S. A. 102, 17717-17722. https://doi.org/10.1073/pnas.0508531102
- Lim, Y.S., Nguyen, M.T.N., Pham, T.X., Huynh, T.T.X., Park, E.M., Choi, D.H., Kang, S.M., Tark, D., and Hwang, S.B. (2022). Hepatitis C virus NS5A protein interacts with telomere length regulation protein: implications for telomere shortening in patients infected with HCV. Mol. Cells 45, 148-157. https://doi.org/10.14348/molcells.2021.0167
- Lin, R., Heylbroeck, C., Pitha, P.M., and Hiscott, J. (1998). Virus-dependent phosphorylation of the IRF-3 transcription factor regulates nuclear translocation, transactivation potential, and proteasome-mediated degradation. Mol. Cell. Biol. 18, 2986-2996. https://doi.org/10.1128/MCB.18.5.2986
- Lin, W., Kim, S.S., Yeung, E., Kamegaya, Y., Blackard, J.T., Kim, K.A., Holtzman, M.J., and Chung, R.T. (2006). Hepatitis C virus core protein blocks interferon signaling by interaction with the STAT1 SH2 domain. J. Virol. 80, 9226-9235. https://doi.org/10.1128/JVI.00459-06
- Lindenbach, B.D. and Rice, C.M. (2005). Unravelling hepatitis C virus replication from genome to function. Nature 436, 933-938. https://doi.org/10.1038/nature04077
- Masaki, T., Matsunaga, S., Takahashi, H., Nakashima, K., Kimura, Y., Ito, M., Matsuda, M., Murayama, A., Kato, T., Hirano, H., et al. (2014). Involvement of hepatitis C virus NS5A hyperphosphorylation mediated by casein kinase I-alpha in infectious virus production. J. Virol. 88, 7541-7555. https://doi.org/10.1128/JVI.03170-13
- Matsumoto, M., Hwang, S.B., Jeng, K.S., Zhu, N., and Lai, M.M. (1996). Homotypic interaction and multimerization of hepatitis C virus core protein. Virology 218, 43-51. https://doi.org/10.1006/viro.1996.0164
- Metz, P., Reuter, A., Bender, S., and Bartenschlager, R. (2013). Interferonstimulated genes and their role in controlling hepatitis C virus. J. Hepatol. 59, 1331-1341. https://doi.org/10.1016/j.jhep.2013.07.033
- Morikawa, K., Lange, C.M., Gouttenoire, J., Meylan, E., Brass, V., Penin, F., and Moradpour, D. (2011). Nonstructural protein 3-4A: the Swiss army knife of hepatitis C virus. J. Viral Hepat. 18, 305-315. https://doi.org/10.1111/j.1365-2893.2011.01451.x
- Nakatsu, Y., Matsuoka, M., Chang, T.H., Otsuki, N., Noda, M., Kimura, H., Sakai, K., Kato, H., Takeda, M., and Kubota, T. (2014). Functionally distinct effects of the C-terminal regions of IKKepsilon and TBK1 on type I IFN production. PLoS One 9, e94999. https://doi.org/10.1371/journal.pone.0094999
- Ng, S.L., Friedman, B.A., Schmid, S., Gertz, J., Myers, R.M., Tenoever, B.R., and Maniatis, T. (2011). IkappaB kinase epsilon (IKK(epsilon)) regulates the balance between type I and type II interferon responses. Proc. Natl. Acad. Sci. U. S. A. 108, 21170-21175. https://doi.org/10.1073/pnas.1119137109
- Nguyen, L.P., Nguyen, T.T.T., Nguyen, H.C., Pham, H.T., Han, K.M., Choi, D.H., Park, E.M., Kang, S.M., Tark, D., Lim, Y.S., et al. (2020). Cortactin interacts with hepatitis C virus core and NS5A proteins: implications for virion assembly. J. Virol. 94, e01306-20.
- Noguchi, T., Satoh, S., Noshi, T., Hatada, E., Fukuda, R., Kawai, A., Ikeda, S., Hijikata, M., and Shimotohno, K. (2001). Effects of mutation in hepatitis C virus nonstructural protein 5A on interferon resistance mediated by inhibition of PKR kinase activity in mammalian cells. Microbiol. Immunol. 45, 829-840. https://doi.org/10.1111/j.1348-0421.2001.tb01322.x
- Oshiumi, H., Sakai, K., Matsumoto, M., and Seya, T. (2010). DEAD/H BOX 3 (DDX3) helicase binds the RIG-I adaptor IPS-1 to up-regulate IFN-betainducing potential. Eur. J. Immunol. 40, 940-948. https://doi.org/10.1002/eji.200940203
- Park, K.J., Choi, S.H., Choi, D.H., Park, J.M., Yie, S.W., Lee, S.Y., and Hwang, S.B. (2003). Hepatitis C virus NS5A protein modulates c-Jun N-terminal kinase through interaction with tumor necrosis factor receptor-associated factor 2. J. Biol. Chem. 278, 30711-30718. https://doi.org/10.1074/jbc.M209623200
- Pavio, N., Taylor, D.R., and Lai, M.M. (2002). Detection of a novel unglycosylated form of hepatitis C virus E2 envelope protein that is located in the cytosol and interacts with PKR. J. Virol. 76, 1265-1272. https://doi.org/10.1128/JVI.76.3.1265-1272.2002
- Perwitasari, O., Cho, H., Diamond, M.S., and Gale, M., Jr. (2011). Inhibitor of kappaB kinase epsilon (IKK(epsilon)), STAT1, and IFIT2 proteins define novel innate immune effector pathway against West Nile virus infection. J. Biol. Chem. 286, 44412-44423. https://doi.org/10.1074/jbc.M111.285205
- Polyak, S.J., Khabar, K.S., Paschal, D.M., Ezelle, H.J., Duverlie, G., Barber, G.N., Levy, D.E., Mukaida, N., and Gretch, D.R. (2001). Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response. J. Virol. 75, 6095-6106. https://doi.org/10.1128/JVI.75.13.6095-6106.2001
- Ray, R.B. and Ray, R. (2001). Hepatitis C virus core protein: intriguing properties and functional relevance. FEMS Microbiol. Lett. 202, 149-156. https://doi.org/10.1111/j.1574-6968.2001.tb10796.x
- Reed, K.E. and Rice, C.M. (2000). Overview of hepatitis C virus genome structure, polyprotein processing, and protein properties. Curr. Top. Microbiol. Immunol. 242, 55-84.
- Reed, K.E., Xu, J., and Rice, C.M. (1997). Phosphorylation of the hepatitis C virus NS5A protein in vitro and in vivo: properties of the NS5A-associated kinase. J. Virol. 71, 7187-7197. https://doi.org/10.1128/jvi.71.10.7187-7197.1997
- Reyes, G.R. (2002). The nonstructural NS5A protein of hepatitis C virus: an expanding, multifunctional role in enhancing hepatitis C virus pathogenesis. J. Biomed. Sci. 9, 187-197. https://doi.org/10.1007/BF02256065
- Saito, I., Miyamura, T., Ohbayashi, A., Harada, H., Katayama, T., Kikuchi, S., Watanabe, Y., Koi, S., Onji, M., and Ohta, Y. (1990). Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. Proc. Natl. Acad. Sci. U. S. A. 87, 6547-6549. https://doi.org/10.1073/pnas.87.17.6547
- Saito, T., Owen, D.M., Jiang, F., Marcotrigiano, J., and Gale, M., Jr. (2008). Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature 454, 523-527. https://doi.org/10.1038/nature07106
- Schroder, M., Baran, M., and Bowie, A.G. (2008). Viral targeting of DEAD box protein 3 reveals its role in TBK1/IKKepsilon-mediated IRF activation. EMBO J. 27, 2147-2157. https://doi.org/10.1038/emboj.2008.143
- Seth, R.B., Sun, L., Ea, C.K., and Chen, Z.J. (2005). Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122, 669-682. https://doi.org/10.1016/j.cell.2005.08.012
- Sharma, S., tenOever, B.R., Grandvaux, N., Zhou, G.P., Lin, R., and Hiscott, J. (2003). Triggering the interferon antiviral response through an IKK-related pathway. Science 300, 1148-1151. https://doi.org/10.1126/science.1081315
- Tanji, Y., Kaneko, T., Satoh, S., and Shimotohno, K. (1995). Phosphorylation of hepatitis C virus-encoded nonstructural protein NS5A. J. Virol. 69, 3980-3986. https://doi.org/10.1128/jvi.69.7.3980-3986.1995
- Tenoever, B.R., Ng, S.L., Chua, M.A., McWhirter, S.M., Garcia-Sastre, A., and Maniatis, T. (2007). Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunity. Science 315, 1274-1278. https://doi.org/10.1126/science.1136567
- Wong, A.H., Tam, N.W., Yang, Y.L., Cuddihy, A.R., Li, S., Kirchhoff, S., Hauser, H., Decker, T., and Koromilas, A.E. (1997). Physical association between STAT1 and the interferon-inducible protein kinase PKR and implications for interferon and double-stranded RNA signaling pathways. EMBO J. 16, 1291-1304. https://doi.org/10.1093/emboj/16.6.1291
- Yu, M. and Levine, S.J. (2011). Toll-like receptor, RIG-I-like receptors and the NLRP3 inflammasome: key modulators of innate immune responses to double-stranded RNA viruses. Cytokine Growth Factor Rev. 22, 63-72. https://doi.org/10.1016/j.cytogfr.2011.02.001
- Yu, S., Chen, J., Wu, M., Chen, H., Kato, N., and Yuan, Z. (2010). Hepatitis B virus polymerase inhibits RIG-I- and Toll-like receptor 3-mediated beta interferon induction in human hepatocytes through interference with interferon regulatory factor 3 activation and dampening of the interaction between TBK1/IKKepsilon and DDX3. J. Gen. Virol. 91, 2080-2090. https://doi.org/10.1099/vir.0.020552-0