Lamin A/C Mutants Disturb Sumo1 Localization and Sumoylation in Vitro and in Vivo

Abstract

A-type lamins A and C are nuclear intermediate filament proteins in which mutations have been implicated in multiple disease phenotypes commonly known as laminopathies. A few studies have implicated sumoylation in the regulation of A-type lamins. Sumoylation is a post-translational protein modification that regulates a wide range of cellular processes through the attachment of small ubiquitin-related modifier (sumo) to various substrates. Here we showed that laminopathy mutants result in the mislocalization of sumo1 both in vitro (C2C12 cells overexpressing mutant lamins A and C) and in vivo (primary myoblasts and myopathic muscle tissue from the LmnaH222P /H222P mouse model). In C2C12 cells, we showed that the trapping of sumo1 in p.Asp192Gly, p.Gln353Lys, and p.Arg386Lys aggregates of lamin A/C correlated with an increased steady-state level of sumoylation. However, lamin A and C did not appear to be modified by sumo1. Our results suggest that mutant lamin A/C alters the dynamics of sumo1 and thus misregulation of sumoylation may be contributing to disease progression in laminopathies.

Post-translational modifications of intermediate filament proteins: mechanisms and functions

“…3a). These findings suggest that defective lamin A sumoylation could possibly contribute to the pathogenesis of familial dilated cardiomyopathy (DCM) in patients carrying lamin A E203G and E203K mutations 96 . Similarly, several DCM-causing lamin A mutants (D192G, Q353K, R386K) formed SUMO-1-containing aggregates 96 .…”

“…These findings suggest that defective lamin A sumoylation could possibly contribute to the pathogenesis of familial dilated cardiomyopathy (DCM) in patients carrying lamin A E203G and E203K mutations 96 . Similarly, several DCM-causing lamin A mutants (D192G, Q353K, R386K) formed SUMO-1-containing aggregates 96 . As these mutants also increased overall nuclear protein sumoylation, it is possible that the sequestered SUMO-1 may have been conjugated to other proteins, to which access by desumoylases may have been prevented by the aggregation.and/or prevented the access of desumoylases to these targets.…”

“…The sumoylation deficient lamin A K201R forms abnormal puncta inside the nuclei or at the nuclear periphery 14 . Laminopathy-associated lamin A mutants, as exemplified by those listed in the figure, are hyposumoylated and exhibit abnormal organization in comparison to normal lamin A 14,96 . b. Sumoylation regulates the solubility of IFs.…”

The Roles of SUMO in Metabolic Regulation

“…A subset of FPLD cases, also called Dunnigan-type familial partial lipodystrophy, or familial partial lipodystrophy type 2 (FPLD2), is caused by mutations in LMNA gene encoding structural nuclear proteins Lamin A and C (Cao and Hegele 2000; Speckman et al 2000). Lamin A/C is sumoylated (Boudreau et al 2012; Zhang and Sarge 2008) and also binds SUMO through a SUMO-interacting motif (SIM) (Moriuchi et al 2016). Lamin A mutations linked to familial partial lipodystrophy alter lamin A sumoylation (Simon et al 2013).…”

Emerging roles of sumoylation in the regulation of actin, microtubules, intermediate filaments, and septins

“…The first hint that lamins were sumoylated came from two‐hybrid experiments showing that lamin A interacted with the SUMO E2 conjugating enzyme, Ubc9p [Zhang et al, ]. Subsequent studies have since confirmed this finding, but with several noteworthy differences between them [Zhang et al, ; Boudreau et al, ; Simon et al, ].…”