2. Academic Validation
  3. SEL1L-HRD1 endoplasmic reticulum-associated degradation controls STING-mediated innate immunity by limiting the size of the activable STING pool

SEL1L-HRD1 endoplasmic reticulum-associated degradation controls STING-mediated innate immunity by limiting the size of the activable STING pool

  • Nat Cell Biol. 2023 May 4. doi: 10.1038/s41556-023-01138-4.
Yewei Ji # 1 2 3,  Yuan Luo # 4 5,  Yating Wu 5,  Yao Sun 5,  Lianfeng Zhao 5,  Zhen Xue 6,  Mengqi Sun 5,  Xiaoqiong Wei 7,  Zinan He 5,  Shuangcheng Alivia Wu 7,  Liangguang Leo Lin 7,  You Lu 7,  Lei Chang 5,  Fei Chen 5,  Siyu Chen 8,  Wei Qian 9,  Xiaoxi Xu 10,  Shengnuo Chen 5,  Dongli Pan 8,  Zhangsen Zhou 7 11,  Sheng Xia 9,  Chih-Chi Andrew Hu 12,  Tingbo Liang 4 5,  Ling Qi 13 14 15
Affiliations

Affiliations

  • 1 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. ywji@zju.edu.cn.
  • 2 Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA. ywji@zju.edu.cn.
  • 3 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. ywji@zju.edu.cn.
  • 4 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 5 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 6 Graduate Program in Nutrition, Cornell University, Ithaca, NY, USA.
  • 7 Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 8 Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, China.
  • 9 Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, China.
  • 10 Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 11 Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
  • 12 Center for Translational Research in Hematologic Malignancies, Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, TX, USA.
  • 13 Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA. lingq@med.umich.edu.
  • 14 Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA. lingq@med.umich.edu.
  • 15 Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA. lingq@med.umich.edu.
  • # Contributed equally.
PMID: 37142791 DOI: 10.1038/s41556-023-01138-4
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.

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