On May 2nd, 2022, Pinglong Xu laboratory published a research article in Nature Cell Biology entitled “A non-canonical cGAS-STING-PERK pathway facilitates the translational program critical for senescence and organ fibrosis.” This seminal work identifies the first non-canonical cGAS–STING pathway, which controls cap-dependent mRNA translation by the PERK–eIF2α axis and is critical in cellular senescence and organ fibrosis.
Innate DNA sensing via the 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 identified the STING-PERK-eIF2α pathway, a previously unknown cGAS-STING mechanism, enabling an innate immunity control of cap-dependent mRNA translation. Upon cGAMP binding, STING at the ER binds and directly activates the ER-located kinase PERK via their intracellular domains, which precedes the 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.
Signaling mechanism and function of the non-canonical cGAS-STING-PERK pathway
Drs. Dan Zhang and Yutong Liu in Xu laboratory and Yezhang Zhu in Shen laboratory are the first authors. Drs. Pinglong Xu, Li Shen and Tingbo Liang are the corresponding authors of this research. This study was collaborated by Drs. Ying Xi, Songying Ouyang, Xin-Hua Feng and other colleagues, sponsored by NSFC Projects and the National Key Research and Development Program of China.
Article links: https://www.nature.com/articles/s41556-022-00894-z
