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

Aurora Paola Borroni, Andrea Emanuelli, Pooja Anil Shah, Nataša Ilić, Liat Apel-Sarid, Biagio Paolini, Dhanoop Manikoth Ayyathan, Praveen Koganti, Gal Levy-Cohen, Michael Blank

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalAging Cell
Volume17
Issue number2
DOIs
Publication statusPublished - Apr 2018

    Fingerprint

Cite this

Borroni, A. P., Emanuelli, A., Shah, P. A., Ilić, N., Apel-Sarid, L., Paolini, B., Manikoth Ayyathan, D., Koganti, P., Levy-Cohen, G., & Blank, M. (2018). Smurf2 regulates stability and the autophagic-lysosomal turnover of lamin A and its disease-associated form progerin. Aging Cell, 17(2). https://doi.org/10.1111/acel.12732