TRIM21 通过促进 GSDMD 寡聚化来调节细胞焦亡。
TRIM21 regulates pyroptotic cell death by promoting Gasdermin D oligomerization.
机构信息
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.
出版信息
Cell Death Differ. 2022 Feb;29(2):439-450. doi: 10.1038/s41418-021-00867-z. Epub 2021 Sep 11.
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.
Gasdermin-D（GSDMD）在被炎性半胱天冬酶切割时是细胞焦亡的执行者，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，除了切割之外，还没有已知的调节 GSDMD 的机制。在这里，我们表明三结构域蛋白 TRIM21 作为 GSDMD 依赖性细胞焦亡的正调节剂。TRIM21 通过其 PRY-SPRY 结构域与 GSDMD 相互作用，在静止细胞中维持 GSDMD 的稳定表达，但在细胞焦亡过程中诱导 GSDMD 的 N 端（GSDMD-N）聚集。TRIM21 缺陷细胞对 NLRP3 或 NLRC4 炎性体激活的细胞死亡反应减少。在小鼠中遗传消融 TRIM21 可防止 LPS 诱导的炎症和葡聚糖硫酸钠诱导的结肠炎。因此，TRIM21 在 GSDMD 介导的细胞焦亡中起着至关重要的作用，可能是控制和治疗炎症相关疾病的可行靶点。
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