TRIM21 regulates pyroptotic cell death by promoting Gasdermin D oligomerization,Cell Death and Differentiation

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TRIM21 regulates pyroptotic cell death by promoting Gasdermin D oligomerization
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2021-09-11 , 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 ₁

Affiliation

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.
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
Division of Natural Science, Duke Kunshan University, Suzhou, Jiangsu, China.
Key Laboratory of Marine Ecosystem Dynamics, Ministry of Natural Resources & Second Institute of Oceanography, Ministry of Natural Resources, Hangzhou, China.
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
Department of Medical Biophysics, University of Toronto, and Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada.
Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
Department of Neurology, Huashan Hospital and Institute of Neurology, Fudan University, Shanghai, China.

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.

中文翻译：

TRIM21 通过促进 Gasdermin D 寡聚化调节细胞焦亡

Gasdermin-D (GSDMD) 是细胞焦亡的刽子手，当它被炎性半胱天冬酶切割时，它在宿主防御和对危险信号的反应中起着至关重要的作用。到目前为止，除了切割外，没有已知的机制可以调节 GSDMD。在这里，我们展示了三方基序蛋白 TRIM21 作为 GSDMD 依赖性细胞焦亡的正调节因子。TRIM21 通过其 PRY-SPRY 结构域与 GSDMD 相互作用，维持 GSDMD 在静息细胞中的稳定表达，但在细胞焦亡期间诱导 GSDMD 的 N 末端 (GSDMD-N) 聚集。响应 NLRP3 或 NLRC4 炎性体激活，TRIM21 缺陷细胞表现出减少的细胞死亡。小鼠中TRIM21的基因消融赋予了对LPS诱导的炎症和葡聚糖硫酸钠诱导的结肠炎的保护作用。所以，

更新日期：2021-09-12

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