先天免疫系统
生物
内部收益率3
免疫系统
癌症研究
癌变
细胞生物学
坦克结合激酶1
癌细胞
信号转导
癌症
免疫学
遗传学
丝裂原活化蛋白激酶激酶
蛋白激酶C
作者
Monisankar Ghosh,Sanjoy Kumar Saha,Julie A Bettke,Rachana Nagar,Alejandro Parrales,Tomoo Iwakuma,Adrianus W. M. van der Velden,Luis Martínez
出处
期刊:Cancer Cell
[Elsevier]
日期:2021-04-01
卷期号:39 (4): 494-508.e5
被引量:143
标识
DOI:10.1016/j.ccell.2021.01.003
摘要
Mutant p53 (mtp53) proteins can exert cancer-promoting gain-of-function activities. We report a mechanism by which mtp53 suppresses both cell-autonomous and non-cell-autonomous signaling to promote cancer cell survival and evasion of tumor immune surveillance. Mtp53 interferes with the function of the cytoplasmic DNA sensing machinery, cGAS-STING-TBK1-IRF3, that activates the innate immune response. Mtp53, but not wild-type p53, binds to TANK-binding protein kinase 1 (TBK1) and prevents the formation of a trimeric complex between TBK1, STING, and IRF3, which is required for activation, nuclear translocation, and transcriptional activity of IRF3. Inactivation of innate immune signaling by mtp53 alters cytokine production, resulting in immune evasion. Restoring TBK1 signaling is sufficient to bypass mtp53 and lead to restored immune cell function and cancer cell eradication. This work is of translational interest because therapeutic approaches that restore TBK1 function could potentially reactivate immune surveillance and eliminate mtp53 tumors.
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