Research ArticleImmunology

The hepatitis C virus protein NS3 suppresses TNF-α–stimulated activation of NF-κB by targeting LUBAC

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Sci. Signal.  17 Nov 2015:
Vol. 8, Issue 403, pp. ra118
DOI: 10.1126/scisignal.aab2159

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How HCV suppresses NF-κB activation

The inflammatory cytokine TNF-α induces antiviral immune responses by stimulating the transcription factor NF-κB. Patients chronically infected with hepatitis C virus (HCV) have increased serum amounts of TNF-α but ineffective immune responses. Chen et al. found that the HCV protein NS3 blocked TNF-α–stimulated NF-κB activation in a human hepatocyte cell line. Through competitive binding, NS3 blocked the interaction between the adaptor protein NEMO and the multiprotein complex LUBAC, which is required for the ubiquitylation of NEMO and the activation of NF-κB. Given the current lack of a vaccine against HCV, developing therapies that target viral proteins is important for controlling infections.

Abstract

The transcription factor nuclear factor κB (NF-κB) is crucial for innate immune defense against viral infections, and its activation requires the ubiquitylation of upstream proteins, including the adaptor protein NEMO (NF-κB essential modulator). Many infectious pathogens, including hepatitis C virus (HCV), inhibit NF-κB signaling in host cells, which promotes pathogen survival. Frequently, HCV-infected individuals develop a chronic infection, which suggests that HCV can subvert host antiviral responses. We found that HCV infection and replication inhibited the activation of NF-κB by the inflammatory cytokine tumor necrosis factor–α (TNF-α), which was mediated by the viral protein NS3 and, to a lesser extent, NS5B. NS3 directly interacted with linear ubiquitin chain assembly complex (LUBAC), competed with NEMO for binding to LUBAC, and inhibited the LUBAC-mediated linear ubiquitylation of NEMO and the subsequent activation of NF-κB. Together, our results highlight an immune evasion strategy adopted by HCV to modulate host antiviral responses and enhance virus survival and persistence.

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