内部收益率3
泛素连接酶
细胞生物学
泛素
先天免疫系统
生物
抑制器
刺
胞浆
平方毫米
干扰素
效应器
坦克结合激酶1
信号转导
免疫系统
细胞培养
基因
免疫学
生物化学
遗传学
工程类
航空航天工程
酶
蛋白激酶C
丝裂原活化蛋白激酶激酶
作者
Monisankar Ghosh,Suchandrima Saha,Jinyu Li,David C. Montrose,Luis A. Martinez
标识
DOI:10.1101/2022.05.26.493595
摘要
Abstract Tumor suppression by p53 is known to involve cell autonomous and non-cell autonomous mechanisms. p53 has been shown to suppress tumor growth by modulating immune system functions, however, the mechanistic basis for this activity is not well understood. Here we report that p53 promotes the degradation of the DNA exonuclease TREX1, resulting in cytosolic dsDNA accumulation. We demonstrate that p53 requires the ubiquitin ligase TRIM24 to induce TREX1 ubiquitin-dependent degradation. The accumulation of cytosolic DNA due to p53’s suppression of TREX1 activates the cytosolic DNA sensor, cGAS and its downstream effectors STING/TBK1/IRF3 resulting in induction of Type I interferons. TREX1 overexpression sufficed to block WTp53 activation of the cGAS/STING pathway. WTp53 mediated induction of type I interferon (IFNB1) response could be suppressed by cGAS/STING knockout. We find that p53’s tumor suppressor activities are compromised by loss of signaling through the cGAS/STING pathway. Thus, our study reveals that p53 utilizes the cGAS/STING innate immune system pathway for both cell intrinsic and cell extrinsic tumor suppressor activities.
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