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.

由ZMPSTE24基因功能丧失突变引起的 prelamin A 加工酶缺陷导致了一系列以法尼基化 prelamin A 积累为特征的早衰性疾病。在此，我们报告说，有缺陷的 prelamin A 加工触发核 RIPK1 依赖性信号传导导致坏死性凋亡和炎症。我们发现，在 ZMPSTE24 缺陷细胞中，积累的 prelamin A 将 RIPK1 招募到细胞核，以促进其在肿瘤坏死因子刺激后激活。激酶激活的 RIPK1 随后促进细胞核中 RIPK3 介导的 MLKL 激活，导致核膜破坏和坏死性凋亡。该信号传导依赖于 prelamin A 法呢基化，它将 prelamin A 锚定到核膜上，作为坏死性凋亡的成核平台。坏死性凋亡的基因失活改善了Zmpste24 ^−/−小鼠的早衰表型。我们的研究结果确定了 ZMPSTE24 缺陷导致的非常规核坏死性凋亡途径，对早衰性疾病具有致病性后果，并表明 RIPK1 作为 prelamin A 相关早衰性疾病的可行靶点。