Nonstructural protein 5B promotes degradation of the NORE1A tumor suppressor to facilitate hepatitis C virus replication.
Nonstructural protein 5B promotes degradation of the NORE1A tumor suppressor to facilitate hepatitis C virus replication.
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DOI：
10.1002/hep.29049
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发表时间：
2017-05
期刊：
影响因子：
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通讯作者：
Kaushik-Basu N
中科院分区：
文献类型：
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作者：
Arora P;Basu A;Schmidt ML;Clark GJ;Donninger H;Nichols DB;Calvisi DF;Kaushik-Basu N
丙型肝炎感染是肝癌发展的常见危险因素。这种效应背后的分子机制仅被部分理解。在这里，我们发现HCV蛋白NS5B直接结合肿瘤抑制因子NORE1A （RASSF5）并促进其蛋白体降解。此外，我们发现NORE1A共定位到HCV病毒复制的位点并抑制这一过程。因此，NORE1A具有抗病毒活性，可被NS5B特异性拮抗。此外，在原始人类样本中，NORE1A蛋白水平的抑制与Ras活性的升高几乎完全相关。因此，NS5B对NORE1A的失活可能是最大限度地复制HCV所必需的，并且可能通过将Ras信号通路从促衰老/凋亡信号通路转移到HCV诱导的肝癌中，从而对HCV诱导的肝癌起主要作用。HCV使用NS5B特异性抑制NORE1A，促进病毒复制和Ras信号的升高。
Hepatitis C infection is a common risk factor for the development of liver cancer. The molecular mechanisms underlying this effect are only partially understood. Here we show that the HCV protein NS5B directly binds to the tumor suppressor NORE1A (RASSF5) and promotes its proteosomal degradation. In addition, we show that NORE1A co-localizes to sites of HCV viral replication and suppresses the process. Thus, NORE1A has anti-viral activity which is specifically antagonized by NS5B. Moreover, the suppression of NORE1A protein levels correlated almost perfectly with elevation of Ras activity in primary human samples. Therefore, NORE1A inactivation by NS5B may be essential for maximal HCV replication and may make a major contribution to HCV induced liver cancer by shifting Ras signaling away from pro-senescent/apoptotic signaling pathways. HCV uses NS5B to specifically suppress NORE1A facilitating viral replication and elevated Ras signaling.