Interaction between the HCV NS3 protein and the host TBK1 protein leads to inhibition of cellular antiviral responses

✍ Scribed by Motoyuki Otsuka; Naoya Kato; Masaru Moriyama; Hiroyoshi Taniguchi; Yue Wang; Narayan Dharel; Takao Kawabe; Masao Omata

• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: English
• Weight: 333 KB
• Volume: 41
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.20666

✦ Synopsis

The persistent nature of hepatitis C virus (HCV) infection suggests that HCV encodes proteins that enable it to overcome host antiviral responses. Toll-like receptor 3 (TLR3)mediated signaling, which recognizes the double-stranded RNA that is produced during viral replication and induces type I interferons, including interferon ␤ (IFN-␤), is crucial to the host defense against viruses. Recent studies suggest that a TIR domain-containing adaptor protein, TRIF, and two protein kinases, TANK-binding kinase-1 (TBK1) and IB kinase-⑀ (IKK⑀), play essential roles in TLR3-mediated IFN-␤ production through the activation of the transcriptional factor interferon regulatory factor 3 (IRF-3). We report that the HCV NS3 protein interacts directly with TBK1, and that this binding results in the inhibition of the association between TBK1 and IRF-3, which leads to the inhibition of

IRF-3 activation. In conclusion, these results suggest the mechanisms of the inhibition of the innate immune responses of HCV infection by NS3 protein. Supplementary material for this article can be found on the HEPATOLOGY website (http

://www.interscience.wiley.com/jpages/ 0270-9139/suppmat/index.html). (HEPATOLOGY 2005;41:1004-1012.)

H epatitis C virus (HCV), which is a positivestranded RNA virus, persistently infects hepatocytes and is a major causative agent of chronic hepatitis, cirrhosis, and hepatocellular carcinoma worldwide. [1][2][3][4] HCV has an approximately 10-kb genome, contains a large open reading frame that encodes a polyprotein precursor of 3,010 to 3,033 amino acids, and has untranslated regions (UTRs) at the 5Ј-and 3Ј-ends of the genome. The putative organization of the HCV ge-nome (ordered from the 5Ј-end) is as follows: the 5Ј-UTR; three or four structural proteins (core, E1, E2/p7); six nonstructural (NS) proteins (NS2, NS3, NS4A, NS4B, NS5A, NS5B); and the 3Ј-UTR. [5][6][7] However, the effects of these proteins on the functions of HCV-infected cells are not fully understood.

Toll-like receptors (TLRs) are germ-line-encoded receptors that play an important role in innate immunity. [8][9][10][11][12] In the lifecycle of RNA viruses, double-stranded RNA (dsRNA) is generated and recognized by TLR3. 13,14 The activation of TLR3 results in the activation of interferon regulatory factor (IRF)-3, which is a key regulator of the induction of type I interferons (IFN), including IFN-␤, which are crucial mediators of the antiviral response. 15,16 Persistent HCV infection probably results from the disruption of host immune responses by HCV proteins. The HCV NS3/4A protein has been reported to block the phosphorylation and effector actions of IRF-3. 17 Although the serine protease activity of NS3 appears to be involved in this blockage, the molecular mechanism of this phenomenon has not been elucidated, partly because of lack of information regarding the molecular components of the dsRNA-triggered signaling pathway that leads to IRF-3 activation.

Recently, the TIR domain-containing protein TRIF was identified as an adaptor molecule that is responsible