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

doi:10.1038/s41556-023-01138-4

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;25(5):726-739. doi: 10.1038/s41556-023-01138-4. Epub 2023 May 4.

Authors

Yewei Ji^#^{1

2

3}, Yuan Luo^#^{4

5}, Yating Wu⁵, Yao Sun⁵, Lianfeng Zhao⁵, Zhen Xue⁶, Mengqi Sun⁵, Xiaoqiong Wei⁷, Zinan He⁵, Shuangcheng Alivia Wu⁷, Liangguang Leo Lin⁷, You Lu⁷, Lei Chang⁵, Fei Chen⁵, Siyu Chen⁸, Wei Qian⁹, Xiaoxi Xu¹⁰, Shengnuo Chen⁵, Dongli Pan⁸, Zhangsen Zhou^{7

11}, Sheng Xia⁹, Chih-Chi Andrew Hu¹², Tingbo Liang^{4

5}, Ling Qi^{13

14

15}

Affiliations

¹ Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
² Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA. [email protected].
³ Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
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. [email protected].
¹⁴ Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA. [email protected].
¹⁵ Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Endoplasmic Reticulum / metabolism
Endoplasmic Reticulum-Associated Degradation*
Immunity, Innate
Proteins / metabolism
Ubiquitin-Protein Ligases* / metabolism

Substances

Ubiquitin-Protein Ligases
Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding