TY - JOUR
T1 - Smurf2 regulates stability and the autophagic–lysosomal turnover of lamin A and its disease-associated form progerin
AU - Borroni, Aurora Paola
AU - Emanuelli, Andrea
AU - Shah, Pooja Anil
AU - Ilić, Nataša
AU - Apel-Sarid, Liat
AU - Paolini, Biagio
AU - Manikoth Ayyathan, Dhanoop
AU - Koganti, Praveen
AU - Levy-Cohen, Gal
AU - Blank, Michael
N1 - Publisher Copyright: © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
PY - 2018/4
Y1 - 2018/4
N2 - 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.
AB - 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.
KW - Hutchinson-Gilford progeria syndrome
KW - Smurf2
KW - autophagy
KW - lamin A
KW - progerin
KW - ubiquitination
UR - http://www.scopus.com/inward/record.url?scp=85041584439&partnerID=8YFLogxK
U2 - https://doi.org/10.1111/acel.12732
DO - https://doi.org/10.1111/acel.12732
M3 - مقالة
C2 - 29405587
SN - 1474-9718
VL - 17
JO - Aging Cell
JF - Aging Cell
IS - 2
M1 - e12732
ER -