Farnesylated prelamin A induces fibroblast polarity defects in premature aging disorders by inhibiting nesprin-2-SUN2 LINC complex function.

Abstract

Disrupted processing of prelamin A causes Hutchinson-Gilford progeria syndrome (HGPS) and related premature aging disorders. The farnesylated prelamin A variant produced in HGPS, termed progerin, alters actin-nuclear interactions mediated by nesprin-2 and SUN2 LINC complexes resulting in defective cell polarization. To explore further how prelamin A causes these cellular defects, we examined other disease-causing mutations that prevent cleavage of lamin A or reduce the activity of the processing enzyme ZMPSTE24. Accumulation of prelamin A or an uncleaved variant in cells reduced diffusional mobilities of nesprin-2 and SUN2 and inhibited their function in cell polarization in a farnesylation-dependent manner. Expression of short carboxyl-terminal tail fragments of prelamin A variants disrupted cell polarity in a farnesylation-dependent fashion. These results show that retention of the farnesyl moiety in the tails of prelamin A or its variants is the common element responsible for disrupting actin force transmission to the nucleus in premature aging syndromes and support the idea that altered function of actin-dependent LINC complexes is a critical component of premature aging.