Defective Prelamin A Processing Promotes Unconventional Necroptosis Driven by Nuclear RIPK1

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2024 Mar 28

PMID 38538837

Authors

Yuanxin Yang

Jian Zhang

Mingming Lv

Na Cui

Bing Shan

Qi Sun

Lingjie Yan

Mengmeng Zhang

Chengyu Zou

Junying Yuan

Daichao Xu

Affiliations

Soon will be listed here.

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.

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