p53 degradation by a coronavirus papain-like protease suppresses type I interferon signaling.
p53 degradation by a coronavirus papain-like protease suppresses type I interferon signaling.
复制标题
冠状病毒类木瓜蛋白酶降解 p53 可抑制 I 型干扰素信号传导。
DOI：
10.1074/jbc.m114.619890
复制
发表时间：
2015-01-30
期刊：
影响因子：
--
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Yuan L;Chen Z;Song S;Wang S;Tian C;Xing G;Chen X;Xiao ZX;He F;Zhang L
背景：冠状病毒PLP抑制先天免疫反应的分子机制尚不清楚。结果：PLP2通过稳定MDM2诱导P53的降解，IRF7是P53的新靶基因。结论：PLP2抑制P53介导的I型干扰素的产生和细胞凋亡，从而保证病毒的生长。意义：我们确定了冠状病毒诱导低剂量干扰素产生的机制。人类冠状病毒感染的特征通常是病毒在宿主细胞中的猖獗复制和严重的免疫病理。最近，冠状病毒类木瓜蛋白水解酶(PLPs)被发现是先天免疫反应的抑制因子。然而，这种抑制的分子机制仍不清楚。在这里，我们提供了人类冠状病毒NL63(HCoV-NL63)非结构蛋白3(HCoV-NL63)的催化结构域PLP2去泛素化和稳定细胞癌蛋白MDM2并诱导P53蛋白酶体降解的证据。同时，我们确定IRF7(干扰素调节因子7)是P53的一个真正的靶基因，它介导P53诱导的I型干扰素的产生和先天免疫反应。PLP2通过促进P53的降解，抑制P53介导的抗病毒反应和细胞凋亡，以确保病毒在感染细胞中的生长。因此，我们的研究揭示了冠状病毒通过抑制P53-IRF7-干扰素β信号而与PLP结合以逃避宿主固有的抗病毒反应。
Background: The molecular mechanism of coronavirus PLPs suppressing the innate immune response remains unclear. Results: PLP2 induces the degradation of p53 through stabilizing MDM2, and IRF7 is a novel target gene of p53. Conclusion: PLP2 inhibits the p53-mediated production of type I IFN and apoptosis to ensure viral growth. Significance: We identify the mechanism with which coronavirus induces the low dosage IFN production. Infection by human coronaviruses is usually characterized by rampant viral replication and severe immunopathology in host cells. Recently, the coronavirus papain-like proteases (PLPs) have been identified as suppressors of the innate immune response. However, the molecular mechanism of this inhibition remains unclear. Here, we provide evidence that PLP2, a catalytic domain of the nonstructural protein 3 of human coronavirus NL63 (HCoV-NL63), deubiquitinates and stabilizes the cellular oncoprotein MDM2 and induces the proteasomal degradation of p53. Meanwhile, we identify IRF7 (interferon regulatory factor 7) as a bona fide target gene of p53 to mediate the p53-directed production of type I interferon and the innate immune response. By promoting p53 degradation, PLP2 inhibits the p53-mediated antiviral response and apoptosis to ensure viral growth in infected cells. Thus, our study reveals that coronavirus engages PLPs to escape from the innate antiviral response of the host by inhibiting p53-IRF7-IFNβ signaling.