Smurf2 regulates stability and the autophagic-lysosomal turnover of lamin A and its disease-associated form progerin

Aging Cell. 2018 Apr;17(2):e12732. doi: 10.1111/acel.12732. Epub 2018 Feb 5.

Abstract

A-lamins, encoded by the LMNA gene, are major structural components of the nuclear lamina coordinating essential cellular processes. Mutations in the LMNA gene and/or alterations in its expression levels have been linked to a distinct subset of human disorders, collectively known as laminopathies, and to cancer. Mechanisms regulating A-lamins are mostly obscure. Here, we identified E3 ubiquitin ligase Smurf2 as a physiological regulator of lamin A and its disease-associated mutant form progerin (LAΔ50), whose expression underlies the development of Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging syndrome. We show that Smurf2 directly binds, ubiquitinates, and negatively regulates the expression of lamin A and progerin in Smurf2 dose- and E3 ligase-dependent manners. Overexpression of catalytically active Smurf2 promotes the autophagic-lysosomal breakdown of lamin A and progerin, whereas Smurf2 depletion increases lamin A levels. Remarkably, acute overexpression of Smurf2 in progeria fibroblasts was able to significantly reduce the nuclear deformability. Furthermore, we demonstrate that the reciprocal relationship between Smurf2 and A-lamins is preserved in different types of mouse and human normal and cancer tissues. These findings establish Smurf2 as an essential regulator of lamin A and progerin and lay a foundation for evaluating the efficiency of progerin clearance by Smurf2 in HGPS, and targeting of the Smurf2-lamin A axis in age-related diseases such as cancer.

Keywords: Hutchinson-Gilford progeria syndrome; Smurf2; autophagy; lamin A; progerin; ubiquitination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging, Premature / physiopathology*
  • Autophagy
  • Humans
  • Lamin Type A / genetics*
  • Lamin Type A / metabolism
  • Lysosomes / metabolism*
  • Progeria / genetics*
  • Transfection
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Lamin Type A
  • prelamin A
  • SMURF2 protein, human
  • Ubiquitin-Protein Ligases