中国科学院上海有机化学研究所Daichao Xu小组发现，核纤层蛋白A加工缺陷促进由核RIPK1诱导的非典型坏死。相关论文于2024年3月27日发表于国际学术期刊《自然—细胞生物学》杂志。

研究人员发现，在ZMPSTE24缺陷细胞中，累积的前核纤层蛋白A会招募RIPK1至细胞核，以促进其在肿瘤坏死因子刺激下的激活。然后，激酶激活的RIPK1在细胞核中促进RIPK3介导的MLKL激活，导致核膜破坏和细胞坏死。这种信号传导依赖于前核纤层蛋白A的法尼基化，法尼基化将前核纤层蛋白A固定在核膜上，作为坏死的成核平台。

遗传性坏死凋亡可改善Zmpste24^-/-小鼠的早衰表型。该研究结果确定了一种由ZMPSTE24缺乏导致的非典型核坏死途径，它在类早衰症中具有致病性，该研究表明RIPK1是治疗前核纤层蛋白A相关类早衰症的潜在靶点。

据介绍，由ZMPSTE24基因功能缺失突变引起的核纤层蛋白A加工酶缺陷，是一系列以法尼基化前核纤层蛋白A积累为特征的早衰症的病因。

附：英文原文

Title: Defective prelamin A processing promotes unconventional necroptosis driven by nuclear RIPK1

Author: Yang, Yuanxin, Zhang, Jian, lv, Mingming, Cui, Na, Shan, Bing, Sun, Qi, Yan, Lingjie, Zhang, Mengmeng, Zou, Chengyu, Yuan, Junying, Xu, Daichao

Issue&Volume: 2024-03-27

Abstract: Defects in the prelamin A processing enzyme caused by loss-of-function mutations in the ZMPSTE24 gene are responsible for a spectrum of progeroid disorders characterized by the accumulation of farnesylated prelamin A. Here we report that defective prelamin A processing triggers nuclear RIPK1-dependent signalling that leads to necroptosis and inflammation. We show that accumulated prelamin A recruits RIPK1 to the nucleus to facilitate its activation upon tumour necrosis factor stimulation in ZMPSTE24-deficient cells. Kinase-activated RIPK1 then promotes RIPK3-mediated MLKL activation in the nucleus, leading to nuclear envelope disruption and necroptosis. This signalling relies on prelamin A farnesylation, which anchors prelamin A to nuclear envelope to serve as a nucleation platform for necroptosis. Genetic inactivation of necroptosis ameliorates the progeroid phenotypes in Zmpste24/ mice. Our findings identify an unconventional nuclear necroptosis pathway resulting from ZMPSTE24 deficiency with pathogenic consequences in progeroid disorder and suggest RIPK1 as a feasible target for prelamin A-associated progeroid disorders.

DOI: 10.1038/s41556-024-01374-2

Source: https://www.nature.com/articles/s41556-024-01374-2