Connexin 43 ubiquitination determines the fate of gap junctions: restrict to survive

2015 ◽  
Vol 43 (3) ◽  
pp. 471-475 ◽  
Author(s):  
Teresa M. Ribeiro-Rodrigues ◽  
Steve Catarino ◽  
Maria J. Pinho ◽  
Paulo Pereira ◽  
Henrique Girao
Keyword(s):  
Plasma Membrane ◽  
Gap Junctions ◽  
Gap Junction ◽  
Intercellular Communication ◽  
Connexin 43 ◽  
Transmembrane Proteins ◽  
Post Translational Modifications ◽  
Gap Junction Intercellular Communication

Connexins (Cxs) are transmembrane proteins that form channels which allow direct intercellular communication (IC) between neighbouring cells via gap junctions. Mechanisms that modulate the amount of channels at the plasma membrane have emerged as important regulators of IC and their de-regulation has been associated with various diseases. Although Cx-mediated IC can be modulated by different mechanisms, ubiquitination has been described as one of the major post-translational modifications involved in Cx regulation and consequently IC. In this review, we focus on the role of ubiquitin and its effect on gap junction intercellular communication.

IL-1β-induced production of metalloproteinases by synovial cells depends on gap junction conductance

2002 ◽  
Vol 282 (6) ◽  
pp. C1254-C1260 ◽  
Author(s):  
Oleg V. Kolomytkin ◽  
Andrew A. Marino ◽  
David D. Waddell ◽  
J. Michael Mathis ◽  
Robert E. Wolf ◽  
...  
Keyword(s):  
Gap Junctions ◽  
Gap Junction ◽  
Intercellular Communication ◽  
Biological Function ◽  
Synovial Cells ◽  
Gap Junction Intercellular Communication ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Junction Conductance

Synovial cells can form networks connected by gap junctions. The purpose of this study was to obtain evidence for a necessary role of gap junction intercellular communication in protein secretion by synovial cells. We developed a novel assay to measure the enzymatic activity of metalloproteinases (MMPs) produced by synovial cells in response to interleukin-1β (IL-1β) and employed the assay to explore the biological function of gap junctions. IL-1β produced a dose-dependent increase in MMP activity that was blocked by exposure to the gap junction inhibitors 18α-glycyrrhetinic acid and octanol for as few as 50 min. The inhibitors produced an immediate and marked reduction in intercellular communication, as assessed by transient current analysis using the nystatin perforated-patch method. These observations suggest that communication through gap junctions early in IL-1β signal transduction is critical to the process of cytokine-regulated secretion of MMPs by synovial cells.

scholarly journals Connexin 43 K63-polyubiquitination on lysines 264 and 303 regulates gap junction internalization

2017 ◽  
Author(s):  
Rachael M. Kells-Andrews ◽  
Rachel A. Margraf ◽  
Charles G. Fisher ◽  
Matthias M. Falk
Keyword(s):  
Plasma Membrane ◽  
Gap Junctions ◽  
Gap Junction ◽  
Connexin 43 ◽  
Room Temperature ◽  
Cell Communication ◽  
Mapk Phosphorylation ◽  
Annular Gap ◽  
Summary Statement ◽  
Triton X

ABSTRACTGap junctions (GJs) assembled from connexin (Cx) proteins play a pivotal role in cell-to-cell communication by forming channels that connect the cytosols of adjacent cells. Connexin 43, the best-studied Cx, is ubiquitously expressed in vertebrates. While phosphorylation is known to regulate multiple aspects of GJ function, much less is known about the role ubiquitination plays in these processes. Here we show by using ubiquitination-type specific antibodies and Cx43 lysine (K) to arginine (R) mutants that a portion of Cx43 in GJs can become K63-polyubiquitinated on K264 and K303. Relevant Cx43 K/R mutants assembled significantly larger GJ plaques, exhibited much longer protein half-lives and were internalization impaired. Interestingly, ubiquitin-deficient Cx43 mutants accumulated as hyper-phosphorylated polypeptides in the plasma membrane, suggesting that K63-polyubiquitination may be triggered by phosphorylation. Phospho-specific Cx43 antibodies revealed that upregulated phosphorylation affected serines 368, 279/282, and 255, well-known regulatory PKC and MAPK phosphorylation sites. Together, these novel findings suggest that upon internalization, some Cx43 in GJs becomes K63-polyubiquitinated, ubiquitination is critical for GJ internalization, and that K63-polyubiquitination may be induced by Cx phosphorylation.Summary StatementHere we show that connexin 43 in gap junctions becomes K63-poly ubiquitinated on lysines 264 and 303 and its requirement for gap junction endocytosis. These novel findings significantly contribute to our understanding of GJ turnover and patho-/physiology.Abbreviations usedAGJannular gap junctionAMSHassociated molecule with the SH3 domain of STAMCMEclathrin-mediated endocytosisCxConnexinCx43Connexin 43DUBdeubiquitinaseGJgap junctionMonoUbmonoubiquitinNedd4-1neural precursor cell expressed developmentally down-regulated protein 4-1PMplasma membranePolyUbpolyubiquitinTPA12-O-Tetradecanoylphorbol 13-AcetateTX-100Triton X-100RTroom temperatureUbubiquitin

scholarly journals Connexin 43 Expression on Peripheral Blood Eosinophils: Role of Gap Junctions in Transendothelial Migration

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Harissios Vliagoftis ◽  
Cory Ebeling ◽  
Ramses Ilarraza ◽  
Salahaddin Mahmudi-Azer ◽  
Melanie Abel ◽  
...  
Keyword(s):  
Gap Junctions ◽  
Gap Junction ◽  
Peripheral Blood ◽  
Connexin 43 ◽  
Transendothelial Migration ◽  
Glycyrrhetinic Acid ◽  
Dependent Manner ◽  
Dye Transfer ◽  
Blood Eosinophils

Eosinophils circulate in the blood and are recruited in tissues during allergic inflammation. Gap junctions mediate direct communication between adjacent cells and may represent a new way of communication between immune cells distinct from communication through cytokines and chemokines. We characterized the expression of connexin (Cx)43 by eosinophils isolated from atopic individuals using RT-PCR, Western blotting, and confocal microscopy and studied the biological functions of gap junctions on eosinophils. The formation of functional gap junctions was evaluated measuring dye transfer using flow cytometry. The role of gap junctions on eosinophil transendothelial migration was studied using the inhibitor 18-a-glycyrrhetinic acid. Peripheral blood eosinophils express Cx43 mRNA and protein. Cx43 is localized not only in the cytoplasm but also on the plasma membrane. The membrane impermeable dye BCECF transferred from eosinophils to epithelial or endothelial cells following coculture in a dose and time dependent fashion. The gap junction inhibitors 18-a-glycyrrhetinic acid and octanol did not have a significant effect on dye transfer but reduced dye exit from eosinophils. The gap junction inhibitor 18-a-glycyrrhetinic acid inhibited eosinophil transendothelial migration in a dose dependent manner. Thus, eosinophils from atopic individuals express Cx43 constitutively and Cx43 may play an important role in eosinophil transendothelial migration and function in sites of inflammation.

Role of connexin 43 in different forms of intercellular communication – gap junctions, extracellular vesicles and tunnelling nanotubes

2017 ◽  
Vol 130 (21) ◽  
pp. 3619-3630 ◽  
Author(s):  
Teresa M. Ribeiro-Rodrigues ◽  
Tânia Martins-Marques ◽  
Sandrine Morel ◽  
Brenda R. Kwak ◽  
Henrique Girão
Keyword(s):  
Gap Junctions ◽  
Extracellular Vesicles ◽  
Intercellular Communication ◽  
Connexin 43 ◽  
Communication Gap
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