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Nature Cell Biology
SEL1L–HRD1 endoplasmic reticulum-associated degradation controls STING-mediated innate immunity by limiting the size of the activable STING pool
Yewei Ji, Yuan Luo, Yating Wu, Yao Sun, Lianfeng Zhao, Zhen Xue, Mengqi Sun, Xiaoqiong Wei, Zinan He, Shuangcheng Alivia Wu, Liangguang Leo Lin, You Lu, Lei Chang, Fei Chen, Siyu Chen, Wei Qian, Xiaoxi Xu, Shengnuo Chen, Dongli Pan, Zhangsen Zhou, Sheng Xia, Chih-Chi Andrew Hu, Tingbo Liang & Ling Qi
Endoplasmatic Reticulum, immunity
Stimulator of interferon genes (STING) orchestrates the production of proinflammatory cytokines in response to cytosolic double-stranded DNA; however, the pathophysiological significance and molecular mechanism underlying the folding and maturation of nascent STING protein at the endoplasmic reticulum (ER) remain unknown. Here we report that the SEL1L–HRD1 protein complex—the most conserved branch of ER-associated degradation (ERAD)—is a negative regulator of the STING innate immunity by ubiquitinating and targeting nascent STING protein for proteasomal degradation in the basal state. SEL1L or HRD1 deficiency in macrophages specifically amplifies STING signalling and immunity against viral infection and tumour growth. Mechanistically, nascent STING protein is a bona fide substrate of SEL1L–HRD1 in the basal state, uncoupled from ER stress or its sensor inositol-requiring enzyme 1α. Hence, our study not only establishes a key role of SEL1L–HRD1 ERAD in innate immunity by limiting the size of the activable STING pool, but identifies a regulatory mechanism and therapeutic approach to targeting STING.