The Mitochondrial Protein MAVS Stabilizes p53 to Suppress Tumorigenesis.
The Mitochondrial Protein MAVS Stabilizes p53 to Suppress Tumorigenesis.
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线粒体蛋白 MAVS 稳定 p53 以抑制肿瘤发生
DOI：
10.1016/j.celrep.2019.12.051
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发表时间：
2020
期刊：
影响因子：
8.8
通讯作者：
Wei Congwen
中科院分区：
文献类型：
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作者：
Zhang Wanchuan;Gong Jing;Yang Huan;Wan Luming;Peng Yumeng;Wang Xiaolin;Sun Jin;Li Feng;Geng Yunqi;Li Dongyu;Liu Ning;Mei Gangwu;Cao Yuan;Yan Qiulin;Li Huilong;Zhang Yanhong;He Xiang;Zhang Qiaozhi;Zhang Rui;Wu Feixiang;Zhong Hui;Wei Congwen
最近的报道显示了线粒体抗病毒信号（MAVS）蛋白在病毒诱导的细胞凋亡中的关键作用，但MAVS在肿瘤发生中的参与仍然知之甚少。在此，我们报告MAVS是p53激活的关键调节因子，对于防止肿瘤发生至关重要。我们发现，MAVS促进p53依赖性细胞死亡的DNA损伤。MAVS与p53相互作用并介导遗传毒性应激下p53线粒体募集。从机制上讲，MAVS通过阻断p53-鼠双微体2（MDM 2）复合物的形成来抑制p53泛素化，从而导致p53的稳定。值得注意的是，与它们的野生型同窝仔相比，MAVS敲除小鼠显示出对氧化偶氮甲烷（AOM）或AOM/葡聚糖硫酸钠盐（DSS）诱导的结肠癌的抗性降低。MAVS表达在人结肠癌组织中显著下调。这些结果揭示了MAVS在DNA损伤反应和肿瘤抑制中的作用。
Recent reports have shown the critical role of the mitochondrial antiviral signaling (MAVS) protein in virus-induced apoptosis, but the involvement of MAVS in tumorigenesis is still poorly understood. Herein, we report that MAVS is a key regulator of p53 activation and is critical for protecting against tumorigenesis. We find that MAVS promotes p53-dependent cell death in response to DNA damage. MAVS interacts with p53 and mediates p53 mitochondrial recruitment under genotoxic stress. Mechanistically, MAVS inhibits p53 ubiquitination by blocking the formation of the p53-murine double-minute 2 (MDM2) complex, leading to the stabilization of p53. Notably, compared with their wild-type littermates, MAVS knockout mice display decreased resistance to azoxymethane (AOM) or AOM/dextran sulfate sodium salt (DSS)-induced colon cancer. MAVS expression is significantly downregulated in human colon cancer tissues. These results unveil roles for MAVS in DNA damage response and tumor suppression.