Hepatitis C virus NS5B triggers an MDA5-mediated innate immune response by producing dsRNA without the replication of viral genomes

被引:2
作者
Dansako, Hiromichi [1 ]
Ikeda, Masanori [2 ]
Ariumi, Yasuo [3 ,4 ]
Togashi, Yosuke [1 ]
Kato, Nobuyuki [1 ]
机构
[1] Okayama Univ, Fac Med Dent & Pharmaceut Sci, Dept Tumor Microenvironm, 2-5-1 Shikata Cho,Kita Ku, Okayama 7008558, Japan
[2] Kagoshima Univ, Joint Res Ctr Human Retrovirus Infect, Div Biol Informat Technol, Kagoshima, Japan
[3] Natl Inst Infect Dis, Management Dept Biosafety, Lab Anim, Tokyo, Japan
[4] Natl Inst Infect Dis, Pathogen Bank, Tokyo, Japan
关键词
double-stranded RNA; hepatitis C virus; innate immunity; RIG-I-like receptor; RNA virus; DEPENDENT RNA-POLYMERASE; DOUBLE-STRANDED-RNA; TOLL-LIKE RECEPTORS; SIGNALING PATHWAY; INTERFERON-BETA; CORE PROTEIN; CELL-LINES; RIG-I; NON-A; LOCALIZATION;
D O I
10.1111/febs.16980
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
During the replication of viral genomes, RNA viruses produce double-stranded RNA (dsRNA), through the activity of their RNA-dependent RNA polymerases (RdRps) as viral replication intermediates. Recognition of viral dsRNA by host pattern recognition receptors - such as retinoic acid-induced gene-I (RIG-I)-like receptors and Toll-like receptor 3 - triggers the production of interferon (IFN)-beta via the activation of IFN regulatory factor (IRF)-3. It has been proposed that, during the replication of viral genomes, each of RIG-I and melanoma differentiation-associated gene 5 (MDA5) form homodimers for the efficient activation of a downstream signalling pathway in host cells. We previously reported that, in the non-neoplastic human hepatocyte line PH5CH8, the RdRp NS5B derived from hepatitis C virus (HCV) could induce IFN-beta expression by its RdRp activity without the actual replication of viral genomes. However, the exact mechanism by which HCV NS5B produced IFN-beta remained unknown. In the present study, we first showed that NS5B derived from another Flaviviridae family member, GB virus B (GBV-B), also possessed the ability to induce IFN-beta in PH5CH8 cells. Similarly, HCV NS5B, but not its G317V mutant, which lacks RdRp activity, induced the dimerization of MDA5 and subsequently the activation of IRF-3. Interestingly, immunofluorescence analysis showed that HCV NS5B produced dsRNA. Like HCV NS5B, GBV-B NS5B also triggered the production of dsRNA and subsequently the dimerization of MDA5. Taken together, our results show that HCV NS5B triggers an MDA5-mediated innate immune response by producing dsRNA without the replication of viral genomes in human hepatocytes.
引用
收藏
页码:1119 / 1130
页数:12
相关论文
共 38 条
  • [1] Characterization of the hepatitis C virus RNA replication complex associated with lipid rafts
    Aizaki, H
    Lee, KJ
    Sung, VMH
    Ishiko, H
    Lai, MMC
    [J]. VIROLOGY, 2004, 324 (02) : 450 - 461
  • [2] Refractory nature of normal human diploid fibroblasts with respect to oncogene-mediated transformation
    Akagi, T
    Sasai, K
    Hanafusa, H
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (23) : 13567 - 13572
  • [3] Functional Regulation of MyD88-Activated Interferon Regulatory Factor 5 by K63-Linked Polyubiquitination
    Balkhi, Mumtaz Yaseen
    Fitzgerald, Katherine A.
    Pitha, Paula M.
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 2008, 28 (24) : 7296 - 7308
  • [4] MDA5 cooperatively forms dimers and ATP-sensitive filaments upon binding double-stranded RNA
    Berke, Ian C.
    Modis, Yorgo
    [J]. EMBO JOURNAL, 2012, 31 (07) : 1714 - 1726
  • [5] Toward a surrogate model for hepatitis C virus: An infectious molecular clone of the GB virus-B hepatitis agent
    Bukh, J
    Apgar, CL
    Yanagi, M
    [J]. VIROLOGY, 1999, 262 (02) : 470 - 478
  • [6] Visualizing a correlation between siRNA localization, cellular uptake, and RNAi in living cells
    Chiu, YL
    Ali, A
    Chu, CY
    Cao, H
    Rana, TM
    [J]. CHEMISTRY & BIOLOGY, 2004, 11 (08): : 1165 - 1175
  • [7] ISOLATION OF A CDNA CLONE DERIVED FROM A BLOOD-BORNE NON-A, NON-B VIRAL-HEPATITIS GENOME
    CHOO, QL
    KUO, G
    WEINER, AJ
    OVERBY, LR
    BRADLEY, DW
    HOUGHTON, M
    [J]. SCIENCE, 1989, 244 (4902) : 359 - 362
  • [8] The C-terminal regulatory domain is the RNA 5′-triphosphate sensor of RIG-I
    Cui, Sheng
    Eisenaecher, Katharina
    Kirchhofer, Axel
    Brzozka, Krzysztof
    Lammens, Alfred
    Lammens, Katja
    Fujita, Takashi
    Conzelmann, Karl-Klaus
    Krug, Anne
    Hopfner, Karl-Peter
    [J]. MOLECULAR CELL, 2008, 29 (02) : 169 - 179
  • [9] Hepatitis C virus proteins exhibit conflicting effects on the interferon system in human hepatocyte cells
    Dansako, H
    Naka, K
    Ikeda, M
    Kato, N
    [J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2005, 336 (02) : 458 - 468
  • [10] Differential activation of interferon-inducible genes by hepatitis C virus core protein mediated by the interferon stimulated response element
    Dansako, H
    Naganuma, A
    Nakamura, T
    Ikeda, F
    Nozaki, A
    Kato, N
    [J]. VIRUS RESEARCH, 2003, 97 (01) : 17 - 30