@article{369cc52367594ddbb0e83b9be896fd1e,
title = "SEL1L–HRD1 endoplasmic reticulum-associated degradation controls STING-mediated innate immunity by limiting the size of the activable STING pool",
abstract = "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.",
keywords = "Endoplasmic Reticulum-Associated Degradation, Ubiquitin-Protein Ligases/metabolism, Proteins/metabolism, Endoplasmic Reticulum/metabolism, Immunity, Innate",
author = "Yewei Ji and Yuan Luo and Yating Wu and Yao Sun and Lianfeng Zhao and Zhen Xue and Mengqi Sun and Xiaoqiong Wei and Zinan He and Wu, {Shuangcheng Alivia} and Lin, {Liangguang Leo} and You Lu and Lei Chang and Fei Chen and Siyu Chen and Wei Qian and Xiaoxi Xu and Shengnuo Chen and Dongli Pan and Zhangsen Zhou and Sheng Xia and Hu, {Chih Chi Andrew} and Tingbo Liang and Ling Qi",
note = "Funding Information: We thank R. Singh (Albert Einstein College of Medicine), M. Komatsu and K. Tanaka (Tokyo Metropolitan Institute of Medical Science) for the Atg7f/fmice; M. Raghavan (University of Michigan Medical School) for the HSV-1 virus; J. Moon (University of Michigan Medical School) for the TLR2 and RIG-1 agonists; M. Kronenberg (La Jolla Institute for Immunology) for the DN32.D3 cell line; and other members of the L.Q. laboratory for comments and technical assistance. This work was supported by R01CA163910 to C.-C.A.H., the National Natural Science Foundation of China (82171731) and Investigator Start-up Fund of the First Affiliated Hospital of Zhejiang University (B20735) to Y.J., the National Natural Science Foundation of China (81871234) to S.X., the National Natural Science Foundation of China (82188102) to T.L. and 1R01DK120047, 1R01DK120330, 1R35GM130292 and the Michigan Protein Folding Diseases Initiative to L.Q. Y.J. was supported in part by American Heart Association Scientist Development Grant 17SDG33670192 and Michigan Nutrition Obesity Research Center Pilot/Feasibility Grant P30DK089503. S.A.W. is supported by American Heart Association Predoctoral Fellowship 828841. L.Q. is the recipient of Junior Faculty, Career Development and Innovative Basic Science awards from the American Diabetes Association. Funding Information: We thank R. Singh (Albert Einstein College of Medicine), M. Komatsu and K. Tanaka (Tokyo Metropolitan Institute of Medical Science) for the Atg7 mice; M. Raghavan (University of Michigan Medical School) for the HSV-1 virus; J. Moon (University of Michigan Medical School) for the TLR2 and RIG-1 agonists; M. Kronenberg (La Jolla Institute for Immunology) for the DN32.D3 cell line; and other members of the L.Q. laboratory for comments and technical assistance. This work was supported by R01CA163910 to C.-C.A.H., the National Natural Science Foundation of China (82171731) and Investigator Start-up Fund of the First Affiliated Hospital of Zhejiang University (B20735) to Y.J., the National Natural Science Foundation of China (81871234) to S.X., the National Natural Science Foundation of China (82188102) to T.L. and 1R01DK120047, 1R01DK120330, 1R35GM130292 and the Michigan Protein Folding Diseases Initiative to L.Q. Y.J. was supported in part by American Heart Association Scientist Development Grant 17SDG33670192 and Michigan Nutrition Obesity Research Center Pilot/Feasibility Grant P30DK089503. S.A.W. is supported by American Heart Association Predoctoral Fellowship 828841. L.Q. is the recipient of Junior Faculty, Career Development and Innovative Basic Science awards from the American Diabetes Association. f/f Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
month = may,
doi = "10.1038/s41556-023-01138-4",
language = "English (US)",
volume = "25",
pages = "726--739",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "5",
}