A non-canonical cGAS–STING–PERK pathway facilitates the translational program critical for senescence and organ fibrosis

• Published in: Nature cell biology Vol. 24; no. 5; pp. 766 - 782
• Main Authors: Zhang, Dan, Liu, Yutong, Zhu, Yezhang, Zhang, Qian, Guan, Hongxing, Liu, Shengduo, Chen, Shasha, Mei, Chen, Chen, Chen, Liao, Zhiyong, Xi, Ying, Ouyang, Songying, Feng, Xin-Hua, Liang, Tingbo, Shen, Li, Xu, Pinglong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2022; Nature Publishing Group
• Subjects: 13/1; 13/109; 13/51; 13/95; 14/32; 38/39; 38/77; 631/250/262; 631/337/574; 631/80/304; 631/80/509; 64/60; 82/80; 82/83; 96/35; 96/63; Autoimmune diseases; Biomedical and Life Sciences; Cancer Research; Cell Biology; Cellular Senescence; Cyclic GMP; Deoxyribonucleic acid; Developmental Biology; DNA; DNA - metabolism; eIF-2 Kinase; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Fibrosis; Humans; Immunity; Immunity, Innate; Infectious diseases; Inflammation; Innate immunity; Interferon; Interferon regulatory factor 3; Kinases; Life Sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Microorganisms; mRNA; Nucleotidyltransferases - genetics; Nucleotidyltransferases - metabolism; Protein Biosynthesis; Protein folding; Protein Serine-Threonine Kinases; Pyruvate Kinase - metabolism; Senescence; Signal Transduction - physiology; Stem Cells; Stimulators; Translation
• ISSN: 1465-7392; 1476-4679; 1476-4679
• DOI: 10.1038/s41556-022-00894-z

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. Zhang et al. report that a non-canonical cGAS–STING pathway activates PERK–eIF2α to elaborate cap-dependent mRNA translation and contributes to senescence and fibrosis.