IRE1a promotes viral infection by conferring resistance to apoptosis

Science Signaling

Volumn 10, Issue 482, 2017, Pages

  Fink, Susan L ^a,b   Jayewickreme, Teshika R ^a   Molony, Ryan D ^a   Iwawaki, Takao ^c   Landis, Charles S ^d   Lindenbach, Brett D ^a   Iwasaki, Akiko ^a,e  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF WASHINGTON   (United States)

^c KANAZAWA MEDICAL UNIVERSITY   (Japan)

^d UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE   (United States)

^e HOWARD HUGHES MEDICAL INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

INTERFERON; MEMBRANE PROTEIN; MICRORNA; MICRORNA 125A; NONSTRUCTURAL PROTEIN 4B; NUCLEASE; PROTEIN BCL 2; PROTEIN IRE1ALPHA; UNCLASSIFIED DRUG; X BOX BINDING PROTEIN 1; ERN1 PROTEIN, HUMAN; MIRN125 MICRORNA, HUMAN; NS4B PROTEIN, FLAVIVIRUS; PROTEIN SERINE THREONINE KINASE; RIBONUCLEASE; VIRAL PROTEIN; XBP1 PROTEIN, MOUSE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIVIRAL RESISTANCE; APOPTOSIS; ARTICLE; CHRONIC HEPATITIS C; CONTROLLED STUDY; CYTOKINE RESPONSE; EMBRYO; ENZYME ACTIVATION; FEMALE; FIBROBLAST; HUMAN; HUMAN CELL; HUMAN TISSUE; LIVER BIOPSY; MACROPHAGE; MALE; MOUSE; NONHUMAN; PRIORITY JOURNAL; VIRUS INFECTION; VIRUS REPLICATION; ANIMAL; CASE CONTROL STUDY; CELL CULTURE; GENETICS; HEPACIVIRUS; HEPATITIS C; HERPES SIMPLEX; KNOCKOUT MOUSE; LIVER; METABOLISM; PATHOGENICITY; PATHOLOGY; PHYSIOLOGY; SIMPLEXVIRUS; VESICULAR STOMATITIS; VESICULAR STOMATITIS INDIANA VIRUS; VIROLOGY;

ANIMALS; APOPTOSIS; CASE-CONTROL STUDIES; CELLS, CULTURED; ENDORIBONUCLEASES; FEMALE; HEPACIVIRUS; HEPATITIS C; HERPES SIMPLEX; HUMANS; LIVER; MALE; MICE; MICE, KNOCKOUT; MICRORNAS; PROTEIN-SERINE-THREONINE KINASES; SIMPLEXVIRUS; VESICULAR STOMATITIS; VESICULAR STOMATITIS INDIANA VIRUS; VIRAL NONSTRUCTURAL PROTEINS; VIRUS REPLICATION; X-BOX BINDING PROTEIN 1;

EID: 85020427287     PISSN: 19450877     EISSN: 19379145     Source Type: Journal    
DOI: 10.1126/scisignal.aai7814     Document Type: Article

References (76)

1. M. R. Thompson, J. J. Kaminski, E. A. Kurt-Jones, K. A. Fitzgerald, Pattern recognition receptors and the innate immune response to viral infection. Viruses 3, 920-940 (2011).
2. A. Pichlmair, C. Reis e Sousa, Innate recognition of viruses. Immunity 27, 370-383 (2007).
3. W. M. Schneider, M. D. Chevillotte, C. M. Rice, Interferon-stimulated genes: A complex web of host defenses. Annu. Rev. Immunol. 32, 513-545 (2014).
4. L. Zhang, A. Wang, Virus-induced ER stress and the unfolded protein response. Front. Plant Sci. 3, 293 (2012).
5. D. Ron, P. Walter, Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8, 519-529 (2007).
6. M. Schröder, R. J. Kaufman, The mammalian unfolded protein response. Annu. Rev. Biochem. 74, 739-789 (2005).
7. P. Walter, D. Ron, The unfolded protein response: From stress pathway to homeostatic regulation. Science 334, 1081-1086 (2011).
8. C. Hetz, F. Martinon, D. Rodriguez, L. H. Glimcher, The unfolded protein response: Integrating stress signals through the stress sensor IRE1a. Physiol. Rev. 91, 1219-1243 (2011).
9. J. Hollien, J. H. Lin, H. Li, N. Stevens, P. Walter, J. S. Weissman, Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J. Cell Biol. 186, 323-331 (2009).
10. J. Hollien, J. S. Weissman, Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 313, 104-107 (2006).
11. F. Martinon, X. Chen, A.-H. Lee, L. H. Glimcher, TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat. Immunol. 11, 411-418 (2010).
12. F. Hu, X. Yu, H. Wang, D. Zuo, C. Guo, H. Yi, B. Tirosh, J. R. Subjeck, X. Qiu, X.-Y. Wang, ER stress and its regulator X-box-binding protein-1 enhance polyIC-induced innate immune response in dendritic cells. Eur. J. Immunol. 41, 1086-1097 (2011).
13. J. A. Smith, M. J. Turner, M. L. DeLay, E. I. Klenk, D. P. Sowders, R. A. Colbert, Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN-b induction via X-box binding protein 1. Eur. J. Immunol. 38, 1194-1203 (2008).
14. J. A. Cho, A.-H. Lee, B. Platzer, B. C. S. Cross, B. M. Gardner, H. De Luca, P. Luong, H. P. Harding, L. H. Glimcher, P. Walter, E. Fiebiger, D. Ron, J. C. Kagan, W. I. Lencer, The unfolded protein response element IRE1a senses bacterial proteins invading the ER to activate RIG-I and innate immune signaling. Cell Host Microbe 13, 558-569 (2013).
15. S. C. Eckard, G. I. Rice, A. Fabre, C. Badens, E. E. Gray, J. L. Hartley, Y. J. Crow, D. B. Stetson, The SKIV2L RNA exosome limits activation of the RIG-I-like receptors. Nat. Immunol. 15, 839-845 (2014).
16. K. Y. Hur, J.-S. So, V. Ruda, M. Frank-Kamenetsky, K. Fitzgerald, V. Koteliansky, T. Iwawaki, L. H. Glimcher, A.-H. Lee, IRE1a activation protects mice against acetaminophen-induced hepatotoxicity. J. Exp. Med. 209, 307-318 (2012).
17. A. Kaser, A.-H. Lee, A. Franke, J. N. Glickman, S. Zeissig, H. Tilg, E. E. Nieuwenhuis, D. E. Higgins, S. Schreiber, L. H. Glimcher, R. S. Blumberg, XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134, 743-756 (2008).
18. Y. Zheng, B. Gao, L. Ye, L. Kong, W. Jing, X. Yang, Z. Wu, L. Ye, Hepatitis C virus non-structural protein NS4B can modulate an unfolded protein response. J. Microbiol. 43, 529-536 (2005).
19. A. M. Reimold, A. Etkin, I. Clauss, A. Perkins, D. S. Friend, J. Zhang, H. F. Horton, A. Scott, S. H. Orkin, M. C. Byrne, M. J. Grusby, L. H. Glimcher, An essential role in liver development for transcription factor XBP-1. Genes Dev. 14, 152-157 (2000).
20. C. Hetz, A.-H. Lee, D. Gonzalez-Romero, P. Thielen, J. Castilla, C. Soto, L. H. Glimcher, Unfolded protein response transcription factor XBP-1 does not influence prion replication or pathogenesis. Proc. Natl. Acad. Sci. U.S.A. 105, 757-762 (2008).
21. J. A. Hobbs, R. H. Schloemer, G. Hommel-Berrey, Z. Brahmi, Caspase-3-like proteases are activated by infection but are not required for replication of vesicular stomatitis virus. Virus Res. 80, 53-65 (2001).
22. J. A. Hobbs, G. Hommel-Berrey, Z. Brahmi, Requirement of caspase-3 for efficient apoptosis induction and caspase-7 activation but not viral replication or cell rounding in cells infected with vesicular stomatitis virus. Hum. Immunol. 64, 82-92 (2003).
23. B. J. Thomson, Viruses and apoptosis. Int. J. Exp. Pathol. 82, 65-76 (2001).
24. M. Høyer-Hansen, M. Jäättelä, Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Differ. 14, 1576-1582 (2007).
25. A. Margariti, H. Li, T. Chen, D. Martin, G. Vizcay-Barrena, S. Alam, E. Karamariti, Q. Xiao, A. Zampetaki, Z. Zhang, W. Wang, Z. Jiang, C. Gao, B. Ma, Y.-G. Chen, G. Cockerill, Y. Hu, Q. Xu, L. Zeng, XBP1 mRNA splicing triggers an autophagic response in endothelial cells through BECLIN-1 transcriptional activation. J. Biol. Chem. 288, 859-872 (2013).
26. A.-H. Lee, N. N. Iwakoshi, L. H. Glimcher, XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol. Cell. Biol. 23, 7448-7459 (2003).
27. D. Baltzis, L.-K. Qu, S. Papadopoulou, J. D. Blais, J. C. Bell, N. Sonenberg, A. E. Koromilas, Resistance to vesicular stomatitis virus infection requires a functional cross talk between the eukaryotic translation initiation factor 2a kinases PERK and PKR. J. Virol. 78, 12747-12761 (2004).
28. H. F. Burnett, T. E. Audas, G. Liang, R. R. Lu, Herpes simplex virus-1 disarms the unfolded protein response in the early stages of infection. Cell Stress Chaperones 17, 473-483 (2012).
29. M. Mulvey, C. Arias, I. Mohr, Maintenance of endoplasmic reticulum (ER) homeostasis in herpes simplex virus type 1-infected cells through the association of a viral glycoprotein with PERK, a cellular ER stress sensor. J. Virol. 81, 3377-3390 (2007).
30. A. Ganguly, S. Basu, P. Chakraborty, S. Chatterjee, A. Sarkar, M. Chatterjee, S. K. Choudhuri, Targeting mitochondrial cell death pathway to overcome drug resistance with a newly developed iron chelate. PLOS ONE 5, e11253 (2010).
31. A. T. Ho, Q. H. Li, R. Hakem, T. W. Mak, E. Zacksenhaus, Coupling of caspase-9 to Apaf1 in response to loss of pRb or cytotoxic drugs is cell-Type-specific. EMBO J. 23, 460-472 (2004).
32. V.-T. Nguyen, J. S. Lee, Z.-J. Qian, Y.-X. Li, K.-N. Kim, S.-J. Heo, Y.-J. Jeon, W. S. Park, I.-W. Choi, J.-Y. Je, W.-K. Jung, Gliotoxin isolated from marine fungus Aspergillus sp. induces apoptosis of human cervical cancer and chondrosarcoma cells. Mar. Drugs 12, 69-87 (2014).
33. J. Pardo, C. Urban, E. M. Galvez, P. G. Ekert, U. Möller, J. Kwon-Chung, M. Lobigs, A. Mullbacher, R. Wallich, C. Borner, M. M. Simon, The mitochondrial protein Bak is pivotal for gliotoxin-induced apoptosis and a critical host factor of Aspergillus fumigatus virulence in mice. J. Cell Biol. 174, 509-519 (2006).
34. E. E. Varfolomeev, M. Schuchmann, V. Luria, N. Chiannilkulchai, J. S. Beckmann, I. L. Mett, D. Rebrikov, V. M. Brodianski, O. C. Kemper, O. Kollet, T. Lapidot, D. Soffer, T. Sobe, K. B. Avraham, T. Goncharov, H. Holtmann, P. Lonai, D. Wallach, Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity 9, 267-276 (1998).
35. A. E. Byrd, I. V. Aragon, J. W. Brewer, MicroRNA-30c-2limits expression of proadaptive factor XBP1 in the unfolded protein response. J. Cell Biol. 196, 689-698 (2012).
36. L. Romero-Ramirez, H. Cao, D. Nelson, E. Hammond, A.-H. Lee, H. Yoshida, K. Mori, L. H. Glimcher, N. C. Denko, A. J. Giaccia, Q.-T. Le, A. C. Koong, XBP1 is essential for survival under hypoxic conditions and is required for tumor growth. Cancer Res. 64, 5943-5947 (2004).
37. A.-H. Lee, N. N. Iwakoshi, K. C. Anderson, L. H. Glimcher, Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc. Natl. Acad. Sci. U.S.A. 100, 9946-9951 (2003).
38. T. Oltersdorf, S. W. Elmore, A. R. Shoemaker, R. C. Armstrong, D. J. Augeri, B. A. Belli, M. Bruncko, T. L. Deckwerth, J. Dinges, P. J. Hajduk, M. K. Joseph, S. Kitada, S. J. Korsmeyer, A. R. Kunzer, A. Letai, C. Li, M. J. Mitten, D. G. Nettesheim, S. Ng, P. M. Nimmer, J. M. OConnor, A. Oleksijew, A. M. Petros, J. C. Reed, W. Shen, S. K. Tahir, C. B. Thompson, K. J. Tomaselli, B. Wang, M. D. Wendt, H. Zhang, S. W. Fesik, S. H. Rosenberg, An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435, 677-681 (2005).
39. J. R. Cubillos-Ruiz, P. C. Silberman, M. R. Rutkowski, S. Chopra, A. Perales-Puchalt, M. Song, S. Zhang, S. E. Bettigole, D. Gupta, K. Holcomb, L. H. Ellenson, T. Caputo, A.-H. Lee, J. R. Conejo-Garcia, L. H. Glimcher, ER stress sensor XBP1 controls anti-Tumor immunity by disrupting dendritic cell homeostasis. Cell 161, 1527-1538 (2015).
40. B. C. Cross, P. J. Bond, P. G. Sadowski, B. K. Jha, J. Zak, J. M. Goodman, R. H. Silverman, T. A. Neubert, I. R. Baxendale, D. Ron, H. P. Harding, The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule. Proc. Natl. Acad. Sci. U.S.A. 109, E869-E878 (2012).
41. D. Acosta-Alvear, Y. Zhou, A. Blais, M. Tsikitis, N. H. Lents, C. Arias, C. J. Lennon, Y. Kluger, B. D. Dynlacht, XBP1 controls diverse cell type-And condition-specific transcriptional regulatory networks. Mol. Cell 27, 53-66 (2007).
42. D. S. Coelho, P. M. Domingos, Physiological roles of regulated Ire1 dependent decay. Front. Genet. 5, 76 (2014).
43. M. Maurel, E. Chevet, Endoplasmic reticulum stress signaling: The microRNA connection. Am. J. Physiol. Cell Physiol. 304, C1117-C1126 (2013).
44. Z. Tong, N. Liu, L. Lin, X. Guo, D. Yang, Q. Zhang, miR-125a-5p inhibits cell proliferation and induces apoptosis in colon cancer via targeting BCL2, BCL2L12 and MCL1. Biomed. Pharmacother. 75, 129-136 (2015).
45. D. Svensson, O. Gidlöf, K. M. Turczyńska, D. Erlinge, S. Albinsson, B.-O. Nilsson, Inhibition of microRNA-125a promotes human endothelial cell proliferation and viability through an antiapoptotic mechanism. J. Vasc. Res. 51, 239-245 (2014).
46. A. Balakrishnan, A. T. Stearns, P. J. Park, J. M. Dreyfuss, S. W. Ashley, D. B. Rhoads, A. Tavakkolizadeh, Upregulation of proapoptotic microRNA mir-125a after massive small bowel resection in rats. Ann. Surg. 255, 747-753 (2012).
47. D. Sir, W.-l. Chen, J. Choi, T. Wakita, T. S. B. Yen, J.-h. Ou, Induction of incomplete autophagic response by hepatitis C virus via the unfolded protein response. Hepatology 48, 1054-1061 (2008).
48. K. Machida, K. Tsukiyama-Kohara, E. Seike, S. Tone, F. Shibasaki, M. Shimizu, H. Takahashi, Y. Hayashi, N. Funata, C. Taya, H. Yonekawa, M. Kohara, Inhibition of cytochrome c release in Fas-mediated signaling pathway in transgenic mice induced to express hepatitis C viral proteins. J. Biol. Chem. 276, 12140-12146 (2001).
49. Y. Kamegaya, Y. Hiasa, L. Zukerberg, N. Fowler, J. T. Blackard, W. Lin, W. H. Choe, E. V. Schmidt, R. T. Chung, Hepatitis C virus acts as a tumor accelerator by blocking apoptosis in a mouse model of hepatocarcinogenesis. Hepatology 41, 660-667 (2005).
50. T. Phan, A. Kohlway, P. Dimberu, A. M. Pyle, B. D. Lindenbach, The acidic domain of hepatitis C virus NS4A contributes to RNA replication and virus particle assembly. J. Virol. 85, 1193-1204 (2011).
51. M. Rebsamen, E. Meylan, J. Curran, J. Tschopp, The antiviral adaptor proteins Cardif and Trif are processed and inactivated by caspases. Cell Death Differ. 15, 1804-1811 (2008).
52. I. Scott, K. L. Norris, The mitochondrial antiviral signaling protein, MAVS, is cleaved during apoptosis. Biochem. Biophys. Res. Commun. 375, 101-106 (2008).
53. M. J. White, K. McArthur, D. Metcalf, R. M. Lane, J. C. Cambier, M. J. Herold, M. F. van Delft, S. Bedoui, G. Lessene, M. E. Ritchie, D. C. S. Huang, B. T. Kile, Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production. Cell 159, 1549-1562 (2014).
54. A. Rongvaux, R. Jackson, C. C. D. Harman, T. Li, A. P. West, M. R. de Zoete, Y. Wu, B. Yordy, S. A. Lakhani, C.-Y. Kuan, T. Taniguchi, G. S. Shadel, Z. J. Chen, A. Iwasaki, R. A. Flavell, Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell 159, 1563-1577 (2014).
55. D. P. Bartel, MicroRNAs: Target recognition and regulatory functions. Cell 136, 215-233 (2009).
56. Y. Chen, F. Brandizzi, IRE1: ER stress sensor and cell fate executor. Trends Cell Biol. 23, 547-555 (2013).
57. J. H. Lin, H. Li, D. Yasumura, H. R. Cohen, C. Zhang, B. Panning, K. M. Shokat, M. M. LaVail, P. Walter, IRE1 signaling affects cell fate during the unfolded protein response. Science 318, 944-949 (2007).
58. J. H. Lin, H. Li, Y. Zhang, D. Ron, P. Walter, Divergent effects of PERK and IRE1 signaling on cell viability. PLOS ONE 4, e4170 (2009).
59. M. Lu, D. A. Lawrence, S. Marsters, D. Acosta-Alvear, P. Kimmig, A. S. Mendez, A. W. Paton, J. C. Paton, P. Walter, A. Ashkenazi, Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis. Science 345, 98-101 (2014).
60. J.-P. Upton, L. Wang, D. Han, E. S. Wang, N. E. Huskey, L. Lim, M. Truitt, M. T. McManus, D. Ruggero, A. Goga, F. R. Papa, S. A. Oakes, IRE1a cleaves select microRNAs during ER stress to derepress translation of proapoptotic Caspase-2. Science 338, 818-822 (2012).
61. D. Han, A. G. Lerner, L. Vande Walle, J.-P. Upton, W. Xu, A. Hagen, B. J. Backes, S. A. Oakes, F. R. Papa, IRE1a kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell 138, 562-575 (2009).
62. A. G. Lerner, J.-P. Upton, P. V. K. Praveen, R. Ghosh, Y. Nakagawa, A. Igbaria, S. Shen, V. Nguyen, B. J. Backes, M. Heiman, N. Heintz, P. Greengard, S. Hui, Q. Tang, A. Trusina, S. A. Oakes, F. R. Papa, IRE1a induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. Cell Metab. 16, 250-264 (2012).
63. J. J. Sandow, L. Dorstyn, L. A. OReilly, M. Tailler, S. Kumar, A. Strasser, P. G. Ekert, ER stress does not cause upregulation and activation of caspase-2 to initiate apoptosis. Cell Death Differ. 21, 475-480 (2014).
64. H. Nishitoh, A. Matsuzawa, K. Tobiume, K. Saegusa, K. Takeda, K. Inoue, S. Hori, A. Kakizuka, H. Ichijo, ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev. 16, 1345-1355 (2002).
65. F. Urano, X. Wang, A. Bertolotti, Y. Zhang, P. Chung, H. P. Harding, D. Ron, Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287, 664-666 (2000).
66. C. Hetz, E. Chevet, H. P. Harding, Targeting the unfolded protein response in disease. Nat. Rev. Drug Discov. 12, 703-719 (2013).
67. T. S. Fung, Y. Liao, D. X. Liu, The endoplasmic reticulum stress sensor IRE1a protects cells from apoptosis induced by the coronavirus infectious bronchitis virus. J. Virol. 88, 12752-12764 (2014).
68. I. H. Hassan, M. S. Zhang, L. S. Powers, J. Q. Shao, J. Baltrusaitis, D. T. Rutkowski, K. Legge, M. M. Monick, Influenza A viral replication is blocked by inhibition of the inositolrequiring enzyme 1 (IRE1) stress pathway. J. Biol. Chem. 287, 4679-4689 (2012).
69. E. F. Foxman, J. A. Storer, K. Vanaja, A. Levchenko, A. Iwasaki, Two interferon-independent double-stranded RNA-induced host defense strategies suppress the common cold virus at warm temperature. Proc. Natl. Acad. Sci. U.S.A. 113, 8496-8501 (2016).
70. T. Iwawaki, R. Akai, S. Yamanaka, K. Kohno, Function of IRE1 a in the placenta is essential for placental development and embryonic viability. Proc. Natl. Acad. Sci. U.S.A. 106, 16657-16662 (2009).
71. T. Ichinohe, H. K. Lee, Y. Ogura, R. Flavell, A. Iwasaki, Inflammasome recognition of influenza virus is essential for adaptive immune responses. J. Exp. Med. 206, 79-87 (2009).
72. P. Desai, S. Person, Incorporation of the green fluorescent protein into the herpes simplex virus type 1 capsid. J. Virol. 72, 7563-7568 (1998).
73. M. Calfon, H. Zeng, F. Urano, J. H. Till, S. R. Hubbard, H. P. Harding, S. G. Clark, D. Ron, IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415, 92-96 (2002).
74. S. Sanjabi, K. J. Williams, S. Saccani, L. Zhou, A. Hoffmann, G. Ghosh, S. Gerondakis, G. Natoli, S. T. Smale, A c-Rel subdomain responsible for enhanced DNA-binding affinity and selective gene activation. Genes Dev. 19, 2138-2151 (2005).
75. K. L. Lipson, R. Ghosh, F. Urano, The role of IRE1a in the degradation of insulin mRNA in pancreatic b-cells. PLOS ONE 3, e1648 (2008).
76. T. Kazakov, F. Yang, H. N. Ramanathan, A. Kohlway, M. S. Diamond, B. D. Lindenbach, Hepatitis C virus RNA replication depends on specific cis-And trans-Acting activities of viral nonstructural proteins. PLOS Pathog. 11, e1004817 (2015).