Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF.
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-beta (TRIF or TICAM-1), an adaptor protein linking TLR3 to kinases responsible for activating IFN regulatory factor 3 (IRF-3) and NF-kappaB, transcription factors controlling a multiplicity of antiviral defenses. NS3/4A-mediated cleavage of TRIF reduces its abundance and inhibits polyI:C-activated signaling through the TLR3 pathway before its bifurcation to IRF-3 and NF-kappaB. This uniquely broad mechanism of immune evasion potentially limits expression of multiple host defense genes, thereby promoting persistent infections with this medically important virus.
Li
Kui
K
Department of Microbiology and Immunology and Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555-1019, USA.
Foy
Eileen
E
Ferreon
Josephine C
JC
Nakamura
Mitsuyasu
M
Ferreon
Allan C M
AC
Ikeda
Masanori
M
Ray
Stuart C
SC
Gale
Michael
M
Lemon
Stanley M
SM
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000595:Amino Acid Sequence; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology; D016174:Hepacivirus / Q000276:immunology*; D006801:Humans; D050838:Interferon Regulatory Factor-3; D008562:Membrane Glycoproteins / Q000502:physiology; D008969:Molecular Sequence Data; D011956:Receptors, Cell Surface / Q000502:physiology; D015398:Signal Transduction; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014157:Transcription Factors / Q000502:physiology; D017361:Viral Nonstructural Proteins / Q000502:physiology*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D033942:Adaptor Proteins, Vesicular Transport; D004268:DNA-Binding Proteins; D050838:Interferon Regulatory Factor-3; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014157:Transcription Factors; D017361:Viral Nonstructural Proteins; C494232:IRF3 protein, human; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus; C470409:TICAM1 protein, human; C495344:TLR3 protein, human