The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China.
Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Nat Cell Biol. 2022 May;24(5):766-782. doi: 10.1038/s41556-022-00894-z. Epub 2022 May 2.
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.
先天 DNA 感应通过环鸟苷酸-腺苷酸合酶刺激干扰素基因（cGAS-STING）机制检测微生物入侵和细胞损伤，从而参与各种人类传染病、自身免疫性疾病和癌症。然而，DNA 感应如何快速和适应性地塑造细胞生理学尚不完全清楚。在这里，我们确定了 STING-PKR 样内质网激酶（PERK）-eIF2α 途径，这是一种以前未知的 cGAS-STING 机制，能够对依赖帽的信使 RNA 翻译进行先天免疫控制。在 cGAMP 结合后，内质网中的 STING 通过其细胞内结构域与内质网定位的激酶 PERK 结合并直接激活 PERK，这先于 TBK1-IRF3 的激活，与未折叠蛋白反应无关。激活的 PERK 磷酸化 eIF2α，形成一个炎症和生存偏好的翻译程序。值得注意的是，这种 STING-PERK-eIF2α 途径是进化上原始的，对细胞衰老和器官纤维化具有生理上的关键作用。通过药理学或遗传学靶向这种非经典的 cGAS-STING 途径可以减轻肺和肾纤维化。总的来说，这些发现确定了一种替代的先天免疫途径及其在器官纤维化中的关键作用，报告了一种先天免疫导向的翻译程序，并提示靶向 STING-PERK 途径治疗纤维化疾病的治疗潜力。
