E3 ubiquitin ligase HECW2 targets PCNA and lamin B1

Biochimica Et Biophysica Acta. Molecular Cell Research
Vidhya KrishnamoorthyVeena K Parnaik

Abstract

Lamins constitute the major architectural proteins of the nuclear lamina that help in maintaining nuclear organization. Mutations in lamins are associated with diverse degenerative diseases, collectively termed laminopathies. HECW2, a HECT-type E3 ubiquitin ligase, is transcriptionally upregulated in HeLa cells expressing Emery-Dreifuss muscular dystrophy-causing-lamin A mutants. However, the role of HECW2 upregulation in mediating downstream effects in lamin mutant-expressing cells was previously unexplored. Here, we show that HECW2 interacts with two lamin A-binding proteins, proliferating cell nuclear antigen (PCNA), via a canonical PCNA-interacting protein (PIP) motif, and lamin B1. HECW2 mediates their ubiquitination and targets them for proteasomal degradation. Cells expressing lamin A mutants G232E and Q294P, in which HECW2 is upregulated, show increased proteasomal degradation of PCNA and lamin B1 most likely mediated by HECW2. Our findings establish HECW2 as an E3 ubiquitin ligase for PCNA and lamin B1 which regulates their levels in laminopathic cells. We also found that HECW2 interacts with wild-type lamin A and ubiquitinates it and this interaction is reduced in case of lamin mutants G232E and Q294P. Our findings su...Continue Reading

Citations

Apr 26, 2019·Current Genetics·Christine J Smoyer, Sue L Jaspersen
Jul 8, 2019·GeroScience·Susana Gonzalo, Nuria Coll-Bonfill
Mar 13, 2020·Nature Communications·Marie-Line DuboisFrançois-Michel Boisvert
Sep 22, 2018·Histochemistry and Cell Biology·Carmen AdriaensTom Misteli
Nov 17, 2020·Frontiers in Physiology·Léa Lescouzères, Pascale Bomont
Aug 21, 2020·The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques·Tyler PeikesMichael S Salman
May 29, 2021·American Journal of Medical Genetics. Part a·Tomoe YanagishitaToshiyuki Yamamoto
May 28, 2021·Frontiers in Cell and Developmental Biology·Shan QiuJun Huang
Jun 22, 2021·Trends in Biochemical Sciences·Laura A Murray-Nerger, Ileana M Cristea
Jul 30, 2021·Journal of Medical Genetics·Anushree AcharyaIsabelle Schrauwen
May 9, 2021·Brain : a Journal of Neurology·Antonella SferraEnrico Bertini

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