TRIM21 regulates pyroptotic cell death by promoting Gasdermin D oligomerization

Wenqing Gao; Yuanyuan Li; Xuehe Liu; Sen Wang; Pucheng Mei; Zijun Chen; Kewei Liu; Suhua Li; Xue-Wei Xu; Jianhua Gan; Jiaxue Wu; Chaoneng Ji; Chen Ding; Xing Liu; Yuping Lai; Housheng Hansen He; Judy Lieberman; Hao Wu; Xiangjun Chen; Jixi Li

doi:10.1038/s41418-021-00867-z

TRIM21 regulates pyroptotic cell death by promoting Gasdermin D oligomerization

Cell Death Differ. 2022 Feb;29(2):439-450. doi: 10.1038/s41418-021-00867-z. Epub 2021 Sep 11.

Authors

Wenqing Gao^#¹, Yuanyuan Li^#¹, Xuehe Liu¹, Sen Wang¹, Pucheng Mei¹, Zijun Chen¹, Kewei Liu², Suhua Li³, Xue-Wei Xu⁴, Jianhua Gan⁵, Jiaxue Wu⁵, Chaoneng Ji⁵, Chen Ding⁵, Xing Liu⁶, Yuping Lai², Housheng Hansen He⁷, Judy Lieberman⁶, Hao Wu⁸, Xiangjun Chen⁹, Jixi Li¹⁰

Affiliations

¹ Department of Neurology, Huashan Hospital and Institute of Neurology, State Key Laboratory of Genetic Engineering, School of Life Sciences, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, China.
² Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
³ Division of Natural Science, Duke Kunshan University, Suzhou, Jiangsu, China.
⁴ Key Laboratory of Marine Ecosystem Dynamics, Ministry of Natural Resources & Second Institute of Oceanography, Ministry of Natural Resources, Hangzhou, China.
⁵ State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
⁶ Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
⁷ Department of Medical Biophysics, University of Toronto, and Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada.
⁸ Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
⁹ Department of Neurology, Huashan Hospital and Institute of Neurology, Fudan University, Shanghai, China. xiangjchen@fudan.edu.cn.
¹⁰ Department of Neurology, Huashan Hospital and Institute of Neurology, State Key Laboratory of Genetic Engineering, School of Life Sciences, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, China. lijixi@fudan.edu.cn.

^# Contributed equally.

Abstract

Gasdermin-D (GSDMD), the executioner of pyroptotic cell death when it is cleaved by inflammatory caspases, plays a crucial role in host defense and the response to danger signals. So far, there are no known mechanisms, other than cleavage, for regulating GSDMD. Here, we show that tripartite motif protein TRIM21 acts as a positive regulator of GSDMD-dependent pyroptosis. TRIM21 interacted with GSDMD via its PRY-SPRY domain, maintaining GSDMD stable expression in resting cells yet inducing the N-terminus of GSDMD (GSDMD-N) aggregation during pyroptosis. TRIM21-deficient cells displayed a reduced cell death in response to NLRP3 or NLRC4 inflammasome activation. Genetic ablation of TRIM21 in mice conferred protection from LPS-induced inflammation and dextran sulfate sodium-induced colitis. Therefore, TRIM21 plays an essential role in GSDMD-mediated pyroptosis and may be a viable target for controlling and treating inflammation-associated diseases.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Inflammasomes / metabolism
Inflammation
Intracellular Signaling Peptides and Proteins* / genetics
Intracellular Signaling Peptides and Proteins* / metabolism
Mice
Phosphate-Binding Proteins / genetics
Phosphate-Binding Proteins / metabolism
Pyroptosis*

Substances

Inflammasomes
Intracellular Signaling Peptides and Proteins
Phosphate-Binding Proteins

Grants and funding

82071782/National Natural Science Foundation of China (National Science Foundation of China)