Lamin A/C mutants disturb sumo1 localization and sumoylation in vitro and in vivo

PLoS One. 2012;7(9):e45918. doi: 10.1371/journal.pone.0045918. Epub 2012 Sep 21.

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 Lmna(H222P/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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Cell Line
  • Chlorocebus aethiops
  • Gene Expression
  • Lamin Type A / genetics*
  • Lamin Type A / metabolism
  • Mice
  • Mice, Transgenic
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Muscular Diseases / genetics
  • Muscular Diseases / metabolism
  • Mutation, Missense*
  • Myoblasts, Skeletal / metabolism
  • Primary Cell Culture
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Processing, Post-Translational*
  • Protein Transport
  • SUMO-1 Protein / metabolism*
  • Sumoylation
  • Ubiquitin-Conjugating Enzymes / metabolism

Substances

  • Lamin Type A
  • Protein Isoforms
  • SUMO-1 Protein
  • Ubiquitin-Conjugating Enzymes
  • ubiquitin-conjugating enzyme UBC9