Permanent farnesylation of lamin A mutants linked to progeria impairs its phosphorylation at serine 22 during interphase

Aging (Albany NY). 2016 Feb;8(2):366-81. doi: 10.18632/aging.100903.


Mutants of lamin A cause diseases including the Hutchinson-Gilford progeria syndrome (HGPS) characterized by premature aging. Lamin A undergoes a series of processing reactions, including farnesylation and proteolytic cleavage of the farnesylated C-terminal domain. The role of cleavage is unknown but mutations that affect this reaction lead to progeria. Here we show that interphase serine 22 phosphorylation of endogenous mutant lamin A (progerin) is defective in cells from HGPS patients. This defect can be mimicked by expressing progerin in human cells and prevented by inhibition of farnesylation. Furthermore, serine 22 phosphorylation of non-farnesylated progerin was enhanced by a mutation that disrupts lamin A head to tail interactions. The phosphorylation of lamin A or non-farnesylated progerin was associated to the formation of spherical intranuclear lamin A droplets that accumulate protein kinases of the CDK family capable of phosphorylating lamin A at serine 22. CDK inhibitors compromised the turnover of progerin, accelerated senescence of HGPS cells and reversed the effects of FTI on progerin levels. We discuss a model of progeria where faulty serine 22 phosphorylation compromises phase separation of lamin A polymers, leading to accumulation of functionally impaired lamin A structures.

Keywords: Hutchinon-Gilford progeria syndrome; cyclin dependent kinases; lamin A; liquid droplets; senescence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Interphase*
  • Lamin Type A / genetics*
  • Lamin Type A / metabolism*
  • Microscopy, Fluorescence
  • Mutagenesis, Site-Directed
  • Mutation
  • Phosphorylation
  • Progeria / genetics*
  • Progeria / metabolism*
  • Protein Prenylation
  • Serine / metabolism


  • Lamin Type A
  • Serine