The Mitochondrial Protein MAVS Stabilizes p53 to Suppress Tumorigenesis
Wanchuan Zhang, Jing Gong, Huan Yang, Luming Wan, Yumeng Peng, Xiaolin Wang, Jin Sun, Feng Li, Yunqi Geng, Dongyu Li, Ning Liu, Gangwu Mei, Yuan Cao, Qiulin Yan, Huilong Li, Yanhong Zhang, Xiang He, Qiaozhi Zhang, Rui Zhang, Feixiang Wu, Hui Zhong, Congwen Wei
Abstract
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.