title: AMSH-mediated deubiquitination of Cx43 regulates internalization and degradation of gap junctions.
abstract: Gap junctions (GJs) are specialized cell-cell contacts formed by connexins (Cxs), which provide direct intercellular communication between eukaryotic cells. Although Cx43 has long been known to be a substrate for ubiquitination, the reversal of this modification by deubiquitylases (DUBs) has never been described. Here we report that the DUB-associated molecule with the SH3 domain of STAM (AMSH) interacts with Cx43 and mediates its deubiquitination. In this study, we demonstrate that Cx43 is modified with lysine 63-linked polyubiquitin chains and that these increase the interaction between Cx43 and AMSH. We also show that AMSH is recruited to GJ plaque sites at the plasma membrane, where it mediates the deubiquitination of Cx43. Using siRNA depletion or overexpression of a catalytically inactive mutant of AMSH, we show that by decreasing Cx43 deubiquitination, both the internalization and degradation rate of Cx43 are increased. Overall, these data strongly suggest that AMSH-mediated deubiquitination of Cx43 protects GJs from degradation.
authors: Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, and Centro de Física Computacional (CFC), Departamento de Física, University of Coimbra, Coimbra, Portugal.
authors: Teresa M
authors: TM
authors: Ribeiro-Rodrigues
authors: Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, and.
authors: Steve
authors: S
authors: Catarino
authors: Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, and.
authors: Carla
authors: C
authors: Marques
authors: Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, and.
authors: João V
authors: JV
authors: Ferreira
authors: Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, and.
authors: Tânia
authors: T
authors: Martins-Marques
authors: Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, and.
authors: Paulo
authors: P
authors: Pereira
authors: Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, and hmgirao@fmed.uc.pt.
authors: Henrique
authors: H
authors: Girão
mesh_terms: D002450:Cell Communication / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D018031:Connexin 43 / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D017629:Gap Junctions / Q000378:metabolism*; D006801:Humans; D025821:Polyubiquitin / Q000378:metabolism; D059748:Proteolysis; D025801:Ubiquitin / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology
chemical_list: D018031:Connexin 43; D056827:Endosomal Sorting Complexes Required for Transport; C486696:STAMBP protein, human; D025801:Ubiquitin; D025821:Polyubiquitin; D043222:Ubiquitin Thiolesterase
keywords: DUB; connexin43; endocytosis; ubiquitin