Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF
Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF
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DOI：
10.1073/pnas.0408824102
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发表时间：
2005-02-22
影响因子：
11.1
通讯作者：
Lemon, SM
中科院分区：
文献类型：
--
作者：
Li, K;Foy, E;Lemon, SM
Toll 样受体 (TLR) 在感染早期结合病原体特异性配体，启动信号通路，导致多种保护性细胞基因的表达。许多病毒已经进化出阻断通过这些信号通路诱导的效应机制的策略，但病毒对关键近端受体相互作用的干扰尚未被描述。我们在这里展示了丙型肝炎病毒（HCV）的 NS3/4A 丝氨酸蛋白酶，一种以其建立持续肝内感染的能力而臭名昭著的病毒，引起含有诱导 IFN-β（TRIF 或 TICAM-1）的 Toll-IL-1 受体结构域的接头的特异性蛋白水解，该接头蛋白将 TLR3 连接到负责激活 IFN 调节因子 3 (IRF-3) 和 NF-kappaB 的激酶，这些转录因子控制着多重抗病毒防御。 NS3/4A 介导的 TRIF 裂解会降低其丰度，并在其分叉为 IRF-3 和 NF-kappaB 之前抑制通过 TLR3 途径的 Polyl:C 激活信号传导。这种独特的广泛的免疫逃避机制可能会限制多种宿主防御基因的表达，从而促进这种医学上重要的病毒的持续感染。
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 polyl: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.