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.
© 2024. The Author(s), under exclusive licence to Springer Nature Limited.