美国UT西南医学中心Ayaz Najafov团队近日取得一项新成果。经过不懈努力，他们的论文发现了在坏死细胞死亡过程中，SIGLEC12介导质膜破裂。2025年11月12日出版的《自然》杂志发表了这项成果。

通过基于CRISPR–Cas9的全基因组敲除方法，小组发现SIGLEC12在PMR步骤中是MLKL下游坏死坏死的关键介质。SIGLEC12敲低或敲除的细胞在坏死诱导的PMR中存在缺陷，并表现为球状形态。在坏死性下垂期间，SIGLEC12经历去磷酸化，与MLKL相互作用，形成细胞质点并组装成原纤维。值得注意的是，SIGLEC12在坏死坏死期间被TMPRSS4切割，产生一个与NINJ1高度同源的20 kDa片段，这一切割事件是坏死坏死期间诱导PMR的必要条件和充分条件。与癌症相关的SIGLEC12变异（Ser458Phe）和在普通人群中发现的变异（Arg528Trp）减弱了TMPRSS4对SIGLEC12的切割。在小鼠细胞中敲除Siglec12不影响PMR，表明其具有物种特异性作用。他们对SIGLEC12作为PMR介质的鉴定扩展了他们对程序性坏死如何执行的理解，并提供了针对人类疾病中这种促炎症形式的细胞死亡的新方法。

据悉，坏死下垂是一种溶解性细胞死亡的形式，在感染和炎症病理中过度激活。最近发现，NINJ1是焦亡、毒素诱导坏死、细胞凋亡和死铁过程中质膜破裂（PMR）的介质，但在坏死细胞死亡过程中PMR的介质尚不清楚。

附：英文原文

Title: SIGLEC12 mediates plasma membrane rupture during necroptotic cell death

Author: Noh, Hyunjin, Hashem, Zeena, Boms, Elena, Najafov, Ayaz

Issue&Volume: 2025-11-12

Abstract: Necroptosis is a form of lytic cell death that is overactivated during infections and in inflammatory pathologies1. NINJ1 was recently found to be a mediator of plasma membrane rupture (PMR) during pyroptosis, toxin-induced necrosis, apoptosis, and ferroptosis2,3, but the mediator of PMR during necroptotic cell death remained unknown. Here, using a CRISPR–Cas9-based genome-wide knockout approach, we identify SIGLEC12 as a key mediator of necroptosis downstream of MLKL at the PMR step. Cells with knockdown or knockout of SIGLEC12 are defective in necroptosis-induced PMR and demonstrate ballooning morphology. During necroptosis, SIGLEC12 undergoes dephosphorylation, interacts with MLKL, forms cytosolic puncta and assembles into fibrils. Notably, SIGLEC12 is cleaved by TMPRSS4 during necroptosis to produce a 20-kDa fragment highly homologous to NINJ1, and this cleavage event is required and sufficient to induce PMR during necroptosis. A SIGLEC12 variant associated with cancer (Ser458Phe) and a variant found in the general human population (Arg528Trp) attenuate SIGLEC12 cleavage by TMPRSS4. Knockout of Siglec12 in mouse cells does not affect PMR, suggesting a species-specific role. Our identification of SIGLEC12 as a mediator of PMR expands our understanding of how programmed necrosis is executed and offers new approaches for targeting this proinflammatory form of cell death in human diseases.

DOI: 10.1038/s41586-025-09741-1

Source: https://www.nature.com/articles/s41586-025-09741-1