厦门大学吴乔等研究人员合作发现，不依赖于切割的全长GSDME介导焦亡。这一研究成果于2024年7月12日在线发表在国际学术期刊《自然—细胞生物》上。

研究人员发现了一种由全长（FL）Gasdermin E（GSDME）介导的、无需蛋白酶切割的焦亡形式。强烈的紫外线-C辐射引发DNA损伤，激活核PARP1，导致大量形成多聚（ADP-核糖）（PAR）聚合物。这些PAR聚合物释放到细胞质中，激活PARP5以促进GSDME的PAR化，导致GSDME构象发生变化，从而解除其自抑制状态。

此外，紫外线-C辐射促进细胞色素c催化的心磷脂过氧化，增加脂质活性氧物种，这些活性氧物种被PAR化的GSDME感知，导致氧化寡聚化和FL-GSDME靶向细胞膜进行穿孔，最终引发焦亡。能够同时刺激FL-GSDME的PAR化和氧化的试剂协同促进焦亡细胞死亡。

总体而言，该研究揭示了一种未曾报道的GSDME在不依赖切割情况下执行细胞死亡的机制，进一步丰富了对FL-GSDME介导的焦亡的理解和范式。

据悉，  GSDM家族蛋白被称为细胞焦亡的执行者，在引发焦亡之前会经历蛋白酶介导的切割。

附：英文原文

Title: Full-length GSDME mediates pyroptosis independent from cleavage

Author: Zhou, Bo, Jiang, Zhi-hong, Dai, Meng-ran, Ai, Yuan-li, Xiao, Li, Zhong, Chuan-qi, Wu, Liu-Zheng, Chen, Qi-tao, Chen, Hang-zi, Wu, Qiao

Issue&Volume: 2024-07-12

Abstract: Gasdermin (GSDM) family proteins, known as the executors of pyroptosis, undergo protease-mediated cleavage before inducing pyroptosis. We here discovered a form of pyroptosis mediated by full-length (FL) GSDME without proteolytic cleavage. Intense ultraviolet-C irradiation-triggered DNA damage activates nuclear PARP1, leading to extensive formation of poly(ADP-ribose) (PAR) polymers. These PAR polymers are released to the cytoplasm, where they activate PARP5 to facilitate GSDME PARylation, resulting in a conformational change in GSDME that relieves autoinhibition. Moreover, ultraviolet-C irradiation promotes cytochrome c-catalysed cardiolipin peroxidation to elevate lipid reactive oxygen species, which is then sensed by PARylated GSDME, leading to oxidative oligomerization and plasma membrane targeting of FL-GSDME for perforation, eventually inducing pyroptosis. Reagents that concurrently stimulate PARylation and oxidation of FL-GSDME, synergistically promoting pyroptotic cell death. Overall, the present findings elucidate an unreported mechanism underlying the cleavage-independent function of GSDME in executing cell death, further enriching the paradigms and understanding of FL-GSDME-mediated pyroptosis.

DOI: 10.1038/s41556-024-01463-2

Source: https://www.nature.com/articles/s41556-024-01463-2