Hutchinson–Gilford progeria syndrome (HGPS) is a premature ageing disease caused by a mutation in LMNA, which encodes A-type nuclear lamins. This mutation results in the expression of a mutant lamin A termed progerin, leading to impaired cell proliferation and premature cellular senescence. Although most lamin-binding proteins are components of the inner nuclear membrane, lamina-associated polypeptide (LAP) 2α interacts with A-type lamins in the nuclear interior. Reduced levels of LAP2α have been reported in cells from HGPS patients and correlate with impaired proliferation; by contrast, loss of LAP2α in proliferating wild-type cells induces hyperproliferation. The molecular mechanisms of this differential effect have been unclear. Now, Roland Foisner and colleagues (Vidak et al., 2018) provide new insight into the regulation of LAP2α function in proliferation. The authors show that HGPS patient fibroblasts and progerin-expressing fibroblasts proliferate faster than their respective control cells, and ectopic LAP2α expression impairs proliferation. By contrast, in later stages in culture, cells that express high levels of progerin and low levels of LAP2α lose nucleoplasmic A-type lamins, and overexpression of LAP2α promotes proliferation. Simultaneous expression of LAP2α and ectopic lamin A, thereby rescuing the lamin A pool in the nuclear interior, reduces proliferation. These findings suggest a dual A-type-lamin-dependent role for LAP2α in cell proliferation during premature aging.
