title: Permanent farnesylation of lamin A mutants linked to progeria impairs its phosphorylation at serine 22 during interphase.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec, H3C 3J7, Canada.|Current address: IBC Generium LLC, Volginsky 601125, Russia.
authors.forename: Olga
authors.initials: O
authors.lastname: Moiseeva
authors.affiliation: Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec, H3C 3J7, Canada.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Lopes-Paciencia
authors.affiliation: Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec, H3C 3J7, Canada.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Huot
authors.affiliation: Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec, H3C 3J7, Canada.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lessard
authors.affiliation: Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec, H3C 3J7, Canada.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Ferbeyre
mesh_terms: D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007399:Interphase; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010766:Phosphorylation; D011371:Progeria / Q000235:genetics* / Q000378:metabolism*; D017368:Protein Prenylation; D012694:Serine / Q000378:metabolism
chemical_list: D034904:Lamin Type A; D012694:Serine
keywords: Hutchinon-Gilford progeria syndrome; cyclin dependent kinases; lamin A; liquid droplets; senescence