%0 Journal Article
%T Smurf2 regulates stability and the autophagic¨Clysosomal turnover of lamin A and its disease©\associated form progerin
%A Andrea Emanuelli
%A Aurora Paola Borroni
%A Biagio Paolini
%A Dhanoop Manikoth Ayyathan
%A Gal Levy©\Cohen
%A Liat Apel©\Sarid
%A Nata£¿a Ili£¿
%A Pooja Anil Shah
%A Praveen Koganti
%J Archive of "Aging Cell".
%D 2018
%R 10.1111/acel.12732
%X 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 (LA¦¤50), 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¨Clysosomal 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¨Clamin A axis in age©\related diseases such as cancer
%K autophagy
%K Hutchinson©\Gilford progeria syndrome
%K lamin A
%K progerin
%K Smurf2
%K ubiquitination
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847874/