Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF

Kui Li, Eileen Foy, Josephine C. Ferreon, Mitsuyasu Nakamura, Allan C.M. Ferreon, Masanori Ikeda, Stuart C. Ray, Michael Gale, Stanley M. Lemon

Research output: Contribution to journalArticle

851 Citations (Scopus)

Abstract

Toll-like receptors (TLRs) bind pathogen-specific ligands early in infection, initiating signaling pathways that lead to expression of multiple protective cellular genes. Many viruses have evolved strategies that block the effector mechanisms induced through these signaling pathways, but viral interference with critical proximal receptor interactions has not been described. We show here that the NS3/4A serine protease of hepatitis C virus (HCV), a virus notorious for its ability to establish persistent intrahepatic infection, causes specific proteolysis of Toll-IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF or TICAM-1), an adaptor protein linking TLR3 to kinases responsible for activating IFN regulatory factor 3 (IRF-3) and NF-κB, transcription factors controlling a multiplicity of antiviral defenses. NS3/4A-mediated cleavage of TRIF reduces its abundance and inhibits polyl:C-activated signaling through the TLR3 pathway before its bifurcation to IRF-3 and NF-κB. This uniquely broad mechanism of immune evasion potentially limits expression of multiple host defense genes, thereby promoting persistent infections with this medically important virus.

Original languageEnglish
Pages (from-to)2992-2997
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number8
DOIs
Publication statusPublished - Feb 22 2005

Keywords

  • IFN
  • IFN regulatory factor 3
  • INF-κB
  • Innate immunity
  • Protease inhibitor

ASJC Scopus subject areas

  • General

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