刺
干扰素基因刺激剂
先天免疫系统
内部收益率3
生物
细胞生物学
内质网
EIF-2激酶
未折叠蛋白反应
坦克结合激酶1
信号转导
蛋白激酶R
干扰素
免疫学
激酶
蛋白激酶A
免疫系统
MAP激酶激酶激酶
丝裂原活化蛋白激酶激酶
航空航天工程
工程类
细胞周期蛋白依赖激酶2
作者
Dan Zhang,Yutong Liu,Yezhang Zhu,Qian Zhang,Hongxing Guan,Shengduo Liu,Shasha Chen,Mei Chen,Chen Chen,Zhiyong Liao,Ying Xi,Songying Ouyang,Xin‐Hua Feng,Yong‐Min Liang,Li Shen,Pinglong Xu
标识
DOI:10.1038/s41556-022-00894-z
摘要
Innate DNA sensing via the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) mechanism surveys microbial invasion and cellular damage and thus participates in various human infectious diseases, autoimmune diseases and cancers. However, how DNA sensing rapidly and adaptively shapes cellular physiology is incompletely known. Here we identify the STING-PKR-like endoplasmic reticulum kinase (PERK)-eIF2α pathway, a previously unknown cGAS-STING mechanism, enabling an innate immunity control of cap-dependent messenger RNA translation. Upon cGAMP binding, STING at the ER binds and directly activates the ER-located kinase PERK via their intracellular domains, which precedes TBK1-IRF3 activation and is irrelevant to the unfolded protein response. The activated PERK phosphorylates eIF2α, forming an inflammatory- and survival-preferred translation program. Notably, this STING-PERK-eIF2α pathway is evolutionarily primitive and physiologically critical to cellular senescence and organ fibrosis. Pharmacologically or genetically targeting this non-canonical cGAS-STING pathway attenuated lung and kidney fibrosis. Collectively, the findings identify an alternative innate immune pathway and its critical role in organ fibrosis, report an innate immunity-directed translation program and suggest the therapeutic potential for targeting the STING-PERK pathway in treating fibrotic diseases.
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