2. Academic Validation
  3. TRIM21 regulates pyroptotic cell death by promoting Gasdermin D oligomerization

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.
Wenqing Gao  # 1,  Yuanyuan Li  # 1,  Xuehe Liu 1,  Sen Wang 1,  Pucheng Mei 1,  Zijun Chen 1,  Kewei Liu 2,  Suhua Li 3,  Xue-Wei Xu 4,  Jianhua Gan 5,  Jiaxue Wu 5,  Chaoneng Ji 5,  Chen Ding 5,  Xing Liu 6,  Yuping Lai 2,  Housheng Hansen He 7,  Judy Lieberman 6,  Hao Wu 8,  Xiangjun Chen 9,  Jixi Li 10
Affiliations

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.
PMID: 34511601 DOI: 10.1038/s41418-021-00867-z
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.

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