Smurf2 regulates stability and the autophagic–lysosomal turnover of lamin A and its disease‐associated form progerin |
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Authors: | 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 |
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Affiliation: | 1. Laboratory of Molecular and Cellular Cancer Biology, Azrieli Faculty of Medicine, Bar‐Ilan University, Safed, Israel;2. Department of Pathology, The Galilee Medical Center, Nahariya, Israel;3. Department of Pathology and Laboratory Medicine, IRCCS Fondazione, Istituto Nazionale dei Tumori, Milan, Italy |
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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. |
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Keywords: | autophagy Hutchinson‐Gilford progeria syndrome lamin A progerin Smurf2 ubiquitination |
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