Defective prelamin A processing promotes unconventional necroptosis driven by nuclear RIPK1

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• Loss-of-function mutations in ZMPSTE24 lead to progeroid disorders due to farnesylated prelamin A accumulation.
• The role of nuclear signaling in these disorders remains incompletely understood.

Purpose of the Study:

• To investigate the signaling pathways triggered by defective prelamin A processing.
• To elucidate the mechanism linking ZMPSTE24 deficiency to cellular pathology and progeroid phenotypes.

Main Methods:

• Utilized ZMPSTE24-deficient cells and Zmpste24-/- mice models.
• Investigated the recruitment and activation of RIPK1 and RIPK3 in the nucleus.
• Assessed the role of prelamin A farnesylation in the observed signaling pathway.
• Examined the impact of necroptosis inhibition on progeroid phenotypes.

Main Results:

• Defective prelamin A processing activates nuclear RIPK1 signaling in response to TNF stimulation.
• Accumulated, farnesylated prelamin A anchors RIPK1 to the nuclear envelope, facilitating its activation and subsequent RIPK3/MLKL-mediated necroptosis.
• Nuclear envelope disruption and necroptosis were observed in ZMPSTE24-deficient cells.
• Inhibiting necroptosis ameliorated progeroid phenotypes in Zmpste24-/- mice.

Conclusions:

• Defective prelamin A processing initiates an unconventional nuclear necroptosis pathway.
• This pathway contributes to the pathogenesis of progeroid disorders associated with ZMPSTE24 deficiency.
• Targeting RIPK1 may offer a therapeutic strategy for prelamin A-associated progeroid disorders.