Hepatitis C virus core protein enhances FADD-mediated apoptosis and suppresses TRADD signaling of tumor necrosis factor receptor.
Hepatitis C virus core protein enhances FADD-mediated apoptosis and suppresses TRADD signaling of tumor necrosis factor receptor.
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DOI：
10.1006/viro.2001.0896
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发表时间：
2001-05
期刊：
影响因子：
3.7
通讯作者：
Nongliao Zhu;C. Ware;Michael M. C. Lai
中科院分区：
文献类型：
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作者：
Nongliao Zhu;C. Ware;Michael M. C. Lai
丙型肝炎病毒（HCV）核心蛋白已被证明与肿瘤坏死因子受体1（TNFR 1）的死亡结构域（DD）相互作用。在这项研究中，我们进一步研究了核心蛋白与TNFR 1信号分子的相互作用，包括FADD，TRADD和TRAF 2，在人胚肾细胞系HEK-293中，过表达HCV核心蛋白。这种表达核心蛋白的细胞系对TNF诱导的细胞凋亡表现出增强的敏感性。通过体外结合和体内免疫共沉淀试验，我们发现HCV核心蛋白与FADD的DD相互作用，并增强FADD过表达诱导的细胞凋亡。这种增强作用可被FADD的显性阴性突变体阻断。相反，核心蛋白不直接与TRADD的DD相互作用，但可以破坏TRADD与TNFR 1的结合。核心蛋白也破坏了TRAF 2向TNFR 1信号复合物的募集。相应地，TRAF 2依赖的蛋白激酶JNK的激活在核心蛋白表达细胞中被抑制。然而，TNF对NF κ B的激活并没有被HCV核心蛋白显著改变，这表明NF κ B激活存在TRAF 2非依赖性途径。这些结果表明，HCV核心蛋白主要通过促进FADD募集至TNFR 1而使细胞对TNF诱导的凋亡敏感。HCV核心蛋白对JNK激活的抑制也可能有助于细胞凋亡倾向的增加。这些结果与其他已发表的研究相比，表明HCV核心蛋白的作用及其潜在机制在不同来源的细胞中有显着差异。
Hepatitis C virus (HCV) core protein has been shown to interact with the death domain (DD) of tumor necrosis factor receptor-1 (TNFR1). In this study, we further examined the interaction of the core protein with the signaling molecules of TNFR1, including FADD, TRADD, and TRAF2, in a human embryonic kidney cell line, HEK-293, that overexpresses the HCV core protein. This core protein-expressing cell line exhibited enhanced sensitivity to TNF-induced apoptosis. By in vitro binding and in vivo coimmunoprecipitation assays, we showed that the HCV core protein interacted with the DD of FADD and enhanced apoptosis induced by FADD overexpression. This enhancement could be blocked by a dominant-negative mutant of FADD. In contrast, the core protein did not directly interact with the DD of TRADD, but could disrupt the binding of TRADD to TNFR1. TRAF2 recruitment to the TNFR1 signaling complex was also disrupted by the core protein. Correspondingly, TRAF2-dependent activation of the protein kinase JNK was suppressed in the core protein-expressing cells. However, NF kappa B activation by TNF was not significantly altered by the HCV core protein, suggesting the existence of TRAF2-independent pathways for NF kappa B activation. These results combined indicate that the HCV core protein sensitizes cells to TNF-induced apoptosis primarily by facilitating FADD recruitment to TNFR1. The inhibition of JNK activation by the HCV core protein may also contribute to the increased propensity of cells for apoptosis. These results, in comparison with other published studies, suggest that the effects of the HCV core protein and their underlying mechanisms vary significantly among cells of different origins.