AMSH-mediated deubiquitination of Cx43 regulates internalization and degradation of gap junctions
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 b...
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Published in | The FASEB journal Vol. 28; no. 11; p. 4629 |
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Format | Journal Article |
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01.11.2014
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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. |
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AbstractList | 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. |
Author | Ferreira, João V Catarino, Steve Pereira, Paulo Girão, Henrique Ribeiro-Rodrigues, Teresa M Marques, Carla Martins-Marques, Tânia |
Author_xml | – sequence: 1 givenname: Teresa M surname: Ribeiro-Rodrigues fullname: Ribeiro-Rodrigues, Teresa M organization: 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 – sequence: 2 givenname: Steve surname: Catarino fullname: Catarino, Steve organization: Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, and – sequence: 3 givenname: Carla surname: Marques fullname: Marques, Carla organization: Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, and – sequence: 4 givenname: João V surname: Ferreira fullname: Ferreira, João V organization: Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, and – sequence: 5 givenname: Tânia surname: Martins-Marques fullname: Martins-Marques, Tânia organization: Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, and – sequence: 6 givenname: Paulo surname: Pereira fullname: Pereira, Paulo organization: Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, and – sequence: 7 givenname: Henrique surname: Girão fullname: Girão, Henrique email: hmgirao@fmed.uc.pt organization: Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, and hmgirao@fmed.uc.pt |
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SubjectTerms | Cell Communication - physiology Cell Membrane - metabolism Connexin 43 - metabolism Endosomal Sorting Complexes Required for Transport - metabolism Gap Junctions - metabolism Humans Polyubiquitin - metabolism Proteolysis Ubiquitin - metabolism Ubiquitin Thiolesterase - metabolism Ubiquitination - physiology |
Title | AMSH-mediated deubiquitination of Cx43 regulates internalization and degradation of gap junctions |
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