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.
Highlights
The nuclear lamina is a fibrous arrangement underneath the inner nuclear membrane that plays an important structural role determining the mechanical properties of the nucleus [1,2]
To study the biology and turnover of progerin, the lamin A mutant protein responsible for Hutchinson-Gilford progeria syndrome, we used retroviral vectors that express the wild type prelamin A, mature lamin A and mutant derivatives (Figure 1A)
Mutation of serine 22 to aspartic acid (S22D) to mimic phosphorylation had a dramatic consequence for Progerin CS distribution and 100% of the cells displayed round foci (Figure 1C)
Summary
The nuclear lamina is a fibrous arrangement underneath the inner nuclear membrane that plays an important structural role determining the mechanical properties of the nucleus [1,2]. Of nuclear lamina starts from longitudinal head-to-tail associations of lamin A soluble dimers. The resulting polymers associate laterally into fibers, and form paracrystals [9] These polymers are resistant to harsh extraction conditions [10] and has been modelled as an elastic solid, resistant to deformation [11]. Both the N- and C-terminus of lamin A controls the solubility of the protein [12] and deletions of either the N-terminus head domain or the C terminus CaaX farnesylation domain impair localization to the nuclear lamina, leading to the formation of intranuclear lamin A aggregates [13]. In addition to mitotic phosphorylation, lamin A is phosphorylated in interphase at multiple sites including the sites phosphorylated during mitosis [16]
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