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.

Gasdermin (GSDM) 家族蛋白被称为焦亡执行者，在诱导焦亡之前会经历蛋白酶介导的切割。我们在这里发现了一种由全长 (FL) GSDME 介导的焦亡形式，无需蛋白水解切割。强烈的紫外线 C 照射引发的 DNA 损伤会激活核 PARP1，导致聚 (ADP-核糖) (PAR) 聚合物的广泛形成。这些 PAR 聚合物被释放到细胞质，在那里它们激活 PARP5 以促进 GSDME PARylation，导致 GSDME 发生构象变化，从而缓解自抑制。此外，紫外线 C 照射促进细胞色素 C 催化的心磷脂过氧化反应，从而提高脂质活性氧，然后被 PARylated GSDME 感知，导致氧化寡聚化和 FL-GSDME 质膜靶向穿孔，最终诱导细胞焦亡。同时刺激 FL-GSDME 的 PARylation 和氧化的试剂，协同促进焦亡细胞死亡。总体而言，目前的研究结果阐明了 GSDME 在执行细胞死亡过程中独立于裂解的功能的未报道机制，进一步丰富了 FL-GSDME 介导的细胞焦亡的范例和理解。