Skip to main content

Degradation of Connexins Through the Proteasomal, Endolysosomal and Phagolysosomal Pathways

The Journal of Membrane Biology volume 245, pages 389–400 (2012)Cite this article

Abstract

Connexins comprise gap junction channels, which create a direct conduit between the cytoplasms of adjacent cells and provide for intercellular communication. Therefore, the level of total cellular connexin protein can have a direct influence on the level of intercellular communication. Control of connexin protein levels can occur through different mechanisms during the connexin life cycle, such as by regulation of connexin gene expression and turnover of existing protein. The degradation of connexins has been extensively studied, revealing proteasomal, endolysosomal and more recently autophagosomal degradation mechanisms that modulate connexin turnover and, subsequently, affect intercellular communication. Here, we review the current knowledge of connexin degradation pathways.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  • Anselmi F, Hernandez VH, Crispino G, Seydel A, Ortolano S, Roper SD, Kessaris N, Richardson W, Rickheit G, Filippov MA, Monyer H, Mammano F (2008) ATP release through connexin hemichannels and gap junction transfer of second messengers propagate Ca2+ signals across the inner ear. Proc Natl Acad Sci USA 105:18770–18775

    PubMed  CAS  Article  Google Scholar 

  • Auth T, Schluter S, Urschel S, Kussmann P, Sonntag S, Hoher T, Kreuzberg MM, Dobrowolski R, Willecke K (2009) The TSG101 protein binds to connexins and is involved in connexin degradation. Exp Cell Res 315:1053–1062

    PubMed  CAS  Article  Google Scholar 

  • Bargiotas P, Monyer H, Schwaninger M (2009) Hemichannels in cerebral ischemia. Curr Mol Med 9:186–194

    PubMed  CAS  Article  Google Scholar 

  • Beardslee MA, Laing JG, Beyer EC, Saffitz JE (1998) Rapid turnover of connexin43 in the adult rat heart. Circ Res 83:629–635

    PubMed  CAS  Article  Google Scholar 

  • Beardslee MA, Lerner DL, Tadros PN, Laing JG, Beyer EC, Yamada KA, Kleber AG, Schuessler RB, Saffitz JE (2000) Dephosphorylation and intracellular redistribution of ventricular connexin43 during electrical uncoupling induced by ischemia. Circ Res 87:656–662

    PubMed  CAS  Article  Google Scholar 

  • Bercovich Z, Rosenberg-Hasson Y, Ciechanover A, Kahana C (1989) Degradation of ornithine decarboxylase in reticulocyte lysate is ATP-dependent but ubiquitin-independent. J Biol Chem 264:15949–15952

    PubMed  CAS  Google Scholar 

  • Berthoud VM, Tadros PN, Beyer EC (2000) Connexin and gap junction degradation. Methods 20:180–187

    PubMed  CAS  Article  Google Scholar 

  • Boassa D, Solan JL, Papas A, Thornton P, Lampe PD, Sosinsky GE (2010) Trafficking and recycling of the connexin43 gap junction protein during mitosis. Traffic 11:1471–1486

    PubMed  CAS  Article  Google Scholar 

  • Bright NA, Gratian MJ, Luzio JP (2005) Endocytic delivery to lysosomes mediated by concurrent fusion and kissing events in living cells. Curr Biol 15:360–365

    PubMed  CAS  Article  Google Scholar 

  • Cherian PP, Siller-Jackson AJ, Gu S, Wang X, Bonewald LF, Sprague E, Jiang JX (2005) Mechanical strain opens connexin 43 hemichannels in osteocytes: a novel mechanism for the release of prostaglandin. Mol Biol Cell 16:3100–3106

    PubMed  CAS  Article  Google Scholar 

  • Colussi C, Rosati J, Straino S, Spallotta F, Berni R, Stilli D, Rossi S, Musso E, Macchi E, Mai A, Sbardella G, Castellano S, Chimenti C, Frustaci A, Nebbioso A, Altucci L, Capogrossi MC, Gaetano C (2011) Nepsilon-lysine acetylation determines dissociation from GAP junctions and lateralization of connexin 43 in normal and dystrophic heart. Proc Natl Acad Sci USA 108:2795–2800

    PubMed  CAS  Article  Google Scholar 

  • Contreras JE, Saéz JC, Bukauskas FF, Bennett MV (2003) Functioning of cx43 hemichannels demonstrated by single channel properties. Cell Commun Adhes 10:245–249

    PubMed  CAS  Google Scholar 

  • Darrow BJ, Laing JG, Lampe PD, Saffitz JE, Beyer EC (1995) Expression of multiple connexins in cultured neonatal rat ventricular myocytes. Circ Res 76:381–387

    PubMed  CAS  Article  Google Scholar 

  • Das Sarma J, Wang F, Koval M (2002) Targeted gap junction protein constructs reveal connexin-specific differences in oligomerization. J Biol Chem 277:20911–20918

    PubMed  CAS  Article  Google Scholar 

  • Das S, Smith TD, Sarma JD, Ritzenthaler JD, Maza J, Kaplan BE, Cunningham LA, Suaud L, Hubbard MJ, Rubenstein RC, Koval M (2009) ERp29 restricts connexin43 oligomerization in the endoplasmic reticulum. Mol Biol Cell 20:2593–2604

    PubMed  CAS  Article  Google Scholar 

  • Davies KJ (2001) Degradation of oxidized proteins by the 20S proteasome. Biochimie 83:301–310

    PubMed  CAS  Article  Google Scholar 

  • Deveraux Q, Ustrell V, Pickart C, Rechsteiner M (1994) A 26 S protease subunit that binds ubiquitin conjugates. J Biol Chem 269:7059–7061

    PubMed  CAS  Google Scholar 

  • Diez JA, Ahmad S, Evans WH (1999) Assembly of heteromeric connexons in guinea-pig liver en route to the Golgi apparatus, plasma membrane and gap junctions. Eur J Biochem 262:142–148

    PubMed  CAS  Article  Google Scholar 

  • Dunn CA, Su V, Lau AF, Lampe PD (2012) Activation of Akt, not connexin 43 protein ubiquitination, regulates gap junction stability. J Biol Chem 287:2600–2607

    PubMed  CAS  Article  Google Scholar 

  • Elsasser S, Gali RR, Schwickart M, Larsen CN, Leggett DS, Muller B, Feng MT, Tubing F, Dittmar GA, Finley D (2002) Proteasome subunit Rpn1 binds ubiquitin-like protein domains. Nat Cell Biol 4:725–730

    PubMed  CAS  Article  Google Scholar 

  • Fairweather N, Bell C, Cochrane S, Chelly J, Wang S, Mostacciuolo ML, Monaco AP, Haites NE (1994) Mutations in the connexin 32 gene in X-linked dominant Charcot-Marie-Tooth disease (CMTX1). Hum Mol Genet 3:29–34

    PubMed  CAS  Article  Google Scholar 

  • Fallon RF, Goodenough DA (1981) Five-hour half-life of mouse liver gap-junction protein. J Cell Biol 90:521–526

    PubMed  CAS  Article  Google Scholar 

  • Fang S, Weissman AM (2004) A field guide to ubiquitylation. Cell Mol Life Sci 61:1546–1561

    PubMed  CAS  Article  Google Scholar 

  • Feng J, Park J, Cron P, Hess D, Hemmings BA (2004) Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase. J Biol Chem 279:41189–41196

    PubMed  CAS  Article  Google Scholar 

  • Fernandes R, Girao H, Pereira P (2004) High glucose down-regulates intercellular communication in retinal endothelial cells by enhancing degradation of connexin 43 by a proteasome-dependent mechanism. J Biol Chem 279:27219–27224

    PubMed  CAS  Article  Google Scholar 

  • Ferrington DA, Sun H, Murray KK, Costa J, Williams TD, Bigelow DJ, Squier TC (2001) Selective degradation of oxidized calmodulin by the 20 S proteasome. J Biol Chem 276:937–943

    PubMed  CAS  Article  Google Scholar 

  • Fong JT, Kells RM, Gumpert AM, Marzillier JY, Davidson MW, Falk MM (2012) Internalized gap junctions are degraded by autophagy. Autophagy 8:794–811

    Article  Google Scholar 

  • Garré JM, Retamal MA, Cassina P, Barbeito L, Bukauskas FF, Saéz JC, Bennett MV, Abudara V (2010) FGF-1 induces ATP release from spinal astrocytes in culture and opens pannexin and connexin hemichannels. Proc Natl Acad Sci USA 107:22659–22664

    PubMed  Article  Google Scholar 

  • Ghoshroy S, Goodenough DA, Sosinsky GE (1995) Preparation, characterization, and structure of half gap junctional layers split with urea and EGTA. J Membr Biol 146:15–28

    PubMed  CAS  Google Scholar 

  • Gilleron J, Fiorini C, Carette D, Avondet C, Falk MM, Segretain D, Pointis G (2008) Molecular reorganization of Cx43, Zo-1 and Src complexes during the endocytosis of gap junction plaques in response to a non-genomic carcinogen. J Cell Sci 121:4069–4078

    PubMed  CAS  Article  Google Scholar 

  • Gilleron J, Carette D, Fiorini C, Dompierre J, Macia E, Denizot JP, Segretain D, Pointis G (2011) The large GTPase dynamin2: a new player in connexin 43 gap junction endocytosis, recycling and degradation. Int J Biochem Cell Biol 43:1208–1217

    PubMed  CAS  Article  Google Scholar 

  • Girao H, Pereira P (2003) Phosphorylation of connexin 43 acts as a stimuli for proteasome-dependent degradation of the protein in lens epithelial cells. Mol Vis 9:24–30

    PubMed  CAS  Google Scholar 

  • Girao H, Pereira P (2007) The proteasome regulates the interaction between Cx43 and ZO-1. J Cell Biochem 102:719–728

    PubMed  CAS  Article  Google Scholar 

  • Girao H, Catarino S, Pereira P (2009) Eps15 interacts with ubiquitinated Cx43 and mediates its internalization. Exp Cell Res 315:3587–3597

    PubMed  CAS  Article  Google Scholar 

  • Glass JR, Gerner EW (1987) Spermidine mediates degradation of ornithine decarboxylase by a non-lysosomal, ubiquitin-independent mechanism. J Cell Physiol 130:133–141

    PubMed  CAS  Article  Google Scholar 

  • Glickman MH, Rubin DM, Fried VA, Finley D (1998) The regulatory particle of the Saccharomyces cerevisiae proteasome. Mol Cell Biol 18:3149–3162

    PubMed  CAS  Google Scholar 

  • Gómez-Hernández JM, de Miguel M, Larrosa B, González D, Barrio LC (2003) Molecular basis of calcium regulation in connexin-32 hemichannels. Proc Natl Acad Sci USA 100:16030–16035

    PubMed  Article  CAS  Google Scholar 

  • González-Noriega A, Grubb JH, Talkad V, Sly WS (1980) Chloroquine inhibits lysosomal enzyme pinocytosis and enhances lysosomal enzyme secretion by impairing receptor recycling. J Cell Biol 85:839–852

    PubMed  Article  Google Scholar 

  • Goodenough DA, Gilula NB (1974) The splitting of hepatocyte gap junctions and zonulae occludentes with hypertonic disaccharides. J Cell Biol 61:575–590

    PubMed  CAS  Article  Google Scholar 

  • Goodenough DA, Paul DL (2003) Beyond the gap: functions of unpaired connexon channels. Nat Rev Mol Cell Biol 4:285–294

    PubMed  CAS  Article  Google Scholar 

  • Goodenough DA, Goliger JA, Paul DL (1996) Connexins, connexons, and intercellular communication. Annu Rev Biochem 65:475–502

    PubMed  CAS  Article  Google Scholar 

  • Govindarajan R, Chakraborty S, Johnson KE, Falk MM, Wheelock MJ, Johnson KR, Mehta PP (2010) Assembly of connexin43 into gap junctions is regulated differentially by E-cadherin and N-cadherin in rat liver epithelial cells. Mol Biol Cell 21:4089–4107

    PubMed  CAS  Article  Google Scholar 

  • Grune T, Reinheckel T, Davies KJ (1997) Degradation of oxidized proteins in mammalian cells. FASEB J 11:526–534

    PubMed  CAS  Google Scholar 

  • Guan X, Ruch RJ (1996) Gap junction endocytosis and lysosomal degradation of connexin43-P2 in WB-F344 rat liver epithelial cells treated with DDT and lindane. Carcinogenesis 17:1791–1798

    PubMed  CAS  Article  Google Scholar 

  • Gumpert AM, Varco JS, Baker SM, Piehl M, Falk MM (2008) Double-membrane gap junction internalization requires the clathrin-mediated endocytic machinery. FEBS Lett 582:2887–2892

    PubMed  CAS  Article  Google Scholar 

  • He LQ, Cai F, Liu Y, Liu MJ, Tan ZP, Pan Q, Fang FY, de Liang S, Wu LQ, Long ZG, Dai HP, Xia K, Xia JH, Zhang ZH (2005) Cx31 is assembled and trafficked to cell surface by ER-Golgi pathway and degraded by proteasomal or lysosomal pathways. Cell Res 15:455–464

    PubMed  CAS  Article  Google Scholar 

  • Hesketh GG, Shah MH, Halperin VL, Cooke CA, Akar FG, Yen TE, Kass DA, Machamer CE, Van Eyk JE, Tomaselli GF (2010) Ultrastructure and regulation of lateralized connexin43 in the failing heart. Circ Res 106:1153–1163

    PubMed  CAS  Article  Google Scholar 

  • Huang T, Zhu Y, Fang X, Chi Y, Kitamura M, Yao J (2010) Gap junctions sensitize cancer cells to proteasome inhibitor MG132-induced apoptosis. Cancer Sci 101:713–721

    PubMed  CAS  Article  Google Scholar 

  • Husnjak K, Elsasser S, Zhang N, Chen X, Randles L, Shi Y, Hofmann K, Walters KJ, Finley D, Dikic I (2008) Proteasome subunit Rpn13 is a novel ubiquitin receptor. Nature 453:481–488

    PubMed  CAS  Article  Google Scholar 

  • Jariel-Encontre I, Pariat M, Martin F, Carillo S, Salvat C, Piechaczyk M (1995) Ubiquitinylation is not an absolute requirement for degradation of c-Jun protein by the 26 S proteasome. J Biol Chem 270:11623–11627

    PubMed  CAS  Article  Google Scholar 

  • Jariel-Encontre I, Bossis G, Piechaczyk M (2008) Ubiquitin-independent degradation of proteins by the proteasome. Biochim Biophys Acta 1786:153–177

    PubMed  CAS  Google Scholar 

  • Jeyakumar M, Dwek RA, Butters TD, Platt FM (2005) Storage solutions: treating lysosomal disorders of the brain. Nat Rev Neurosci 6:713–725

    PubMed  Google Scholar 

  • Kelly SM, VanSlyke JK, Musil LS (2007) Regulation of ubiquitin-proteasome system mediated degradation by cytosolic stress. Mol Biol Cell 18:4279–4291

    PubMed  CAS  Article  Google Scholar 

  • Kimura K, Nishida T (2010) Role of the ubiquitin-proteasome pathway in downregulation of the gap-junction protein connexin43 by TNF-α in human corneal fibroblasts. Invest Ophthalmol Vis Sci 51:1943–1947

    PubMed  Article  Google Scholar 

  • Kjenseth A, Fykerud T, Rivedal E, Leithe E (2010) Regulation of gap junction intercellular communication by the ubiquitin system. Cell Signal 22:1267–1273

    PubMed  CAS  Article  Google Scholar 

  • Kjenseth A, Fykerud TA, Sirnes S, Bruun J, Kolberg M, Yohannes Z, Omori Y, Rivedal E, Leithe E (2012) The gap junction channel protein connexin43 is covalently modified and regulated by SUMOylation. J Biol Chem 287:15851–15861

    PubMed  CAS  Article  Google Scholar 

  • Knight MM, McGlashan SR, Garcia M, Jensen CG, Poole CA (2009) Articular chondrocytes express connexin 43 hemichannels and P2 receptors—a putative mechanoreceptor complex involving the primary cilium? J Anat 214:275–283

    PubMed  CAS  Article  Google Scholar 

  • Komatsu M, Ichimura Y (2010) Physiological significance of selective degradation of p62 by autophagy. FEBS Lett 584:1374–1378

    PubMed  CAS  Article  Google Scholar 

  • Koval M (2006) Pathways and control of connexin oligomerization. Trends Cell Biol 16:159–166

    PubMed  CAS  Article  Google Scholar 

  • Laing JG, Beyer EC (1995) The gap junction protein connexin43 is degraded via the ubiquitin proteasome pathway. J Biol Chem 270:26399–26403

    PubMed  CAS  Article  Google Scholar 

  • Laing JG, Tadros PN, Westphale EM, Beyer EC (1997) Degradation of connexin43 gap junctions involves both the proteasome and the lysosome. Exp Cell Res 236:482–492

    PubMed  CAS  Article  Google Scholar 

  • Laing JG, Tadros PN, Green K, Saffitz JE, Beyer EC (1998) Proteolysis of connexin43-containing gap junctions in normal and heat-stressed cardiac myocytes. Cardiovasc Res 38:711–718

    PubMed  CAS  Article  Google Scholar 

  • Laird DW (2006) Life cycle of connexins in health and disease. Biochem J 394:527–543

    PubMed  CAS  Article  Google Scholar 

  • Laird DW (2008) Closing the gap on autosomal dominant connexin-26 and connexin-43 mutants linked to human disease. J Biol Chem 283:2997–3001

    PubMed  CAS  Article  Google Scholar 

  • Laird DW, Puranam KL, Revel JP (1991) Turnover and phosphorylation dynamics of connexin43 gap junction protein in cultured cardiac myocytes. Biochem J 273(pt 1):67–72

    PubMed  CAS  Google Scholar 

  • Lan Z, Kurata WE, Martyn KD, Jin C, Lau AF (2005) Novel rab GAP-like protein, CIP85, interacts with connexin43 and induces its degradation. Biochemistry 44:2385–2396

    PubMed  CAS  Article  Google Scholar 

  • Langlois S, Cowan KN, Shao Q, Cowan BJ, Laird DW (2010) The tumor-suppressive function of connexin43 in keratinocytes is mediated in part via interaction with caveolin-1. Cancer Res 70:4222–4232

    PubMed  CAS  Article  Google Scholar 

  • Leithe E, Rivedal E (2004a) Epidermal growth factor regulates ubiquitination, internalization and proteasome-dependent degradation of connexin43. J Cell Sci 117:1211–1220

    PubMed  CAS  Article  Google Scholar 

  • Leithe E, Rivedal E (2004b) Ubiquitination and down-regulation of gap junction protein connexin-43 in response to 12-O-tetradecanoylphorbol 13-acetate treatment. J Biol Chem 279:50089–50096

    PubMed  CAS  Article  Google Scholar 

  • Leithe E, Brech A, Rivedal E (2006) Endocytic processing of connexin43 gap junctions: a morphological study. Biochem J 393:59–67

    PubMed  CAS  Article  Google Scholar 

  • Leithe E, Kjenseth A, Sirnes S, Stenmark H, Brech A, Rivedal E (2009) Ubiquitylation of the gap junction protein connexin-43 signals its trafficking from early endosomes to lysosomes in a process mediated by Hrs and Tsg101. J Cell Sci 122:3883–3893

    PubMed  CAS  Article  Google Scholar 

  • Leithe E, Sirnes S, Fykerud T, Kjenseth A, Rivedal E (2012) Endocytosis and post-endocytic sorting of connexins. Biochim Biophys Acta 1818:1870–1879

    PubMed  CAS  Article  Google Scholar 

  • Li X, Su V, Kurata WE, Jin C, Lau AF (2008) A novel connexin43-interacting protein, CIP75, which belongs to the UbL-UBA protein family, regulates the turnover of connexin43. J Biol Chem 283:5748–5759

    PubMed  CAS  Article  Google Scholar 

  • Lichtenstein A, Minogue PJ, Beyer EC, Berthoud VM (2011) Autophagy: a pathway that contributes to connexin degradation. J Cell Sci 124:910–920

    PubMed  CAS  Article  Google Scholar 

  • Locke D, Bian S, Li H, Harris AL (2009) Post-translational modifications of connexin26 revealed by mass spectrometry. Biochem J 424:385–398

    PubMed  CAS  Article  Google Scholar 

  • Lubke T, Lobel P, Sleat DE (2009) Proteomics of the lysosome. Biochim Biophys Acta 1793:625–635

    PubMed  Article  CAS  Google Scholar 

  • Mari M, Bujny MV, Zeuschner D, Geerts WJ, Griffith J, Petersen CM, Cullen PJ, Klumperman J, Geuze HJ (2008) SNX1 defines an early endosomal recycling exit for sortilin and mannose 6-phosphate receptors. Traffic 9:380–393

    PubMed  CAS  Article  Google Scholar 

  • Martin PE, Evans WH (2004) Incorporation of connexins into plasma membranes and gap junctions. Cardiovasc Res 62:378–387

    PubMed  CAS  Article  Google Scholar 

  • Maza J, Mateescu M, Das Sarma J, Koval M (2003) Differential oligomerization of endoplasmic reticulum–retained connexin43/connexin32 chimeras. Cell Commun Adhes 10:319–322

    PubMed  CAS  Google Scholar 

  • Maza J, Das Sarma J, Koval M (2005) Defining a minimal motif required to prevent connexin oligomerization in the endoplasmic reticulum. J Biol Chem 280:21115–21121

    PubMed  CAS  Article  Google Scholar 

  • Mazet F, Wittenberg BA, Spray DC (1985) Fate of intercellular junctions in isolated adult rat cardiac cells. Circ Res 56:195–204

    PubMed  CAS  Article  Google Scholar 

  • Mitra S, Annamalai L, Chakraborty S, Johnson K, Song XH, Batra SK, Mehta PP (2006) Androgen-regulated formation and degradation of gap junctions in androgen-responsive human prostate cancer cells. Mol Biol Cell 17:5400–5416

    PubMed  CAS  Article  Google Scholar 

  • Murakami Y, Matsufuji S, Kameji T, Hayashi S, Igarashi K, Tamura T, Tanaka K, Ichihara A (1992) Ornithine decarboxylase is degraded by the 26S proteasome without ubiquitination. Nature 360:597–599

    PubMed  CAS  Article  Google Scholar 

  • Murray SA, Larsen WJ, Trout J, Donta ST (1981) Gap junction assembly and endocytosis correlated with patterns of growth in a cultured adrenocortical tumor cell (SW-13). Cancer Res 41:4063–4074

    PubMed  CAS  Google Scholar 

  • Musil LS, Le AC, VanSlyke JK, Roberts LM (2000) Regulation of connexin degradation as a mechanism to increase gap junction assembly and function. J Biol Chem 275:25207–25215

    PubMed  CAS  Article  Google Scholar 

  • Naus CC, Laird DW (2010) Implications and challenges of connexin connections to cancer. Nat Rev Cancer 10:435–441

    PubMed  CAS  Article  Google Scholar 

  • Naus CC, Hearn S, Zhu D, Nicholson BJ, Shivers RR (1993) Ultrastructural analysis of gap junctions in C6 glioma cells transfected with connexin43 cDNA. Exp Cell Res 206:72–84

    PubMed  CAS  Article  Google Scholar 

  • Orlowski M, Wilk S (2003) Ubiquitin-independent proteolytic functions of the proteasome. Arch Biochem Biophys 415:1–5

    PubMed  CAS  Article  Google Scholar 

  • Park DJ, Wallick CJ, Martyn KD, Lau AF, Jin C, Warn-Cramer BJ (2007) Akt phosphorylates connexin43 on Ser373, a “mode-1” binding site for 14–3-3. Cell Commun Adhes 14:211–226

    PubMed  CAS  Article  Google Scholar 

  • Peters NS, Green CR, Poole-Wilson PA, Severs NJ (1993) Reduced content of connexin43 gap junctions in ventricular myocardium from hypertrophied and ischemic human hearts. Circulation 88:864–875

    PubMed  CAS  Article  Google Scholar 

  • Piehl M, Lehmann C, Gumpert A, Denizot JP, Segretain D, Falk MM (2007) Internalization of large double-membrane intercellular vesicles by a clathrin-dependent endocytic process. Mol Biol Cell 18:337–347

    PubMed  CAS  Article  Google Scholar 

  • Puri V, Watanabe R, Dominguez M, Sun X, Wheatley CL, Marks DL, Pagano RE (1999) Cholesterol modulates membrane traffic along the endocytic pathway in sphingolipid-storage diseases. Nat Cell Biol 1:386–388

    PubMed  CAS  Article  Google Scholar 

  • Qin H, Shao Q, Curtis H, Galipeau J, Belliveau DJ, Wang T, Alaoui-Jamali MA, Laird DW (2002) Retroviral delivery of connexin genes to human breast tumor cells inhibits in vivo tumor growth by a mechanism that is independent of significant gap junctional intercellular communication. J Biol Chem 277:29132–29138

    PubMed  CAS  Article  Google Scholar 

  • Qin H, Shao Q, Igdoura SA, Alaoui-Jamali MA, Laird DW (2003) Lysosomal and proteasomal degradation play distinct roles in the life cycle of Cx43 in gap junctional intercellular communication-deficient and -competent breast tumor cells. J Biol Chem 278:30005–30014

    PubMed  CAS  Article  Google Scholar 

  • Rahman S, Carlile G, Evans WH (1993) Assembly of hepatic gap junctions. Topography and distribution of connexin 32 in intracellular and plasma membranes determined using sequence-specific antibodies. J Biol Chem 268:1260–1265

    PubMed  CAS  Google Scholar 

  • Rutz ML, Hülser DF (2001) Supramolecular dynamics of gap junctions. Eur J Cell Biol 80:20–30

    PubMed  CAS  Article  Google Scholar 

  • Saftig P, Klumperman J (2009) Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function. Nat Rev Mol Cell Biol 10:623–635

    PubMed  CAS  Article  Google Scholar 

  • Salameh A (2006) Life cycle of connexins: regulation of connexin synthesis and degradation. Adv Cardiol 42:57–70

    PubMed  CAS  Article  Google Scholar 

  • Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–1101

    PubMed  CAS  Article  Google Scholar 

  • Sasaki T, Garant PR (1986) Fate of annular gap junctions in the papillary cells of the enamel organ in the rat incisor. Cell Tissue Res 246:523–530

    PubMed  CAS  Article  Google Scholar 

  • Sato M, Jiao Q, Honda T, Kurotani R, Toyota E, Okumura S, Takeya T, Minamisawa S, Lanier SM, Ishikawa Y (2009) Activator of G protein signaling 8 (AGS8) is required for hypoxia-induced apoptosis of cardiomyocytes: role of G betagamma and connexin 43 (Cx43). J Biol Chem 284:31431–31440

    PubMed  CAS  Article  Google Scholar 

  • Scemes E, Spray DC, Meda P (2009) Connexins, pannexins, innexins: novel roles of “hemi-channels.”. Pflugers Arch 457:1207–1226

    PubMed  CAS  Article  Google Scholar 

  • Segretain D, Falk MM (2004) Regulation of connexin biosynthesis, assembly, gap junction formation, and removal. Biochim Biophys Acta 1662:3–21

    PubMed  CAS  Article  Google Scholar 

  • Segretain D, Decrouy X, Dompierre J, Escalier D, Rahman N, Fiorini C, Mograbi B, Siffroi JP, Huhtaniemi I, Fenichel P, Pointis G (2003) Sequestration of connexin43 in the early endosomes: an early event of Leydig cell tumor progression. Mol Carcinog 38:179–187

    PubMed  CAS  Article  Google Scholar 

  • Severs NJ, Shovel KS, Slade AM, Powell T, Twist VW, Green CR (1989) Fate of gap junctions in isolated adult mammalian cardiomyocytes. Circ Res 65:22–42

    PubMed  CAS  Article  Google Scholar 

  • Severs NJ, Bruce AF, Dupont E, Rothery S (2008) Remodelling of gap junctions and connexin expression in diseased myocardium. Cardiovasc Res 80:9–19

    PubMed  CAS  Article  Google Scholar 

  • Shearer D, Ens W, Standing K, Valdimarsson G (2008) Posttranslational modifications in lens fiber connexins identified by off-line-HPLC MALDI-quadrupole time-of-flight mass spectrometry. Invest Ophthalmol Vis Sci 49:1553–1562

    PubMed  Article  Google Scholar 

  • Shringarpure R, Grune T, Mehlhase J, Davies KJ (2003) Ubiquitin conjugation is not required for the degradation of oxidized proteins by proteasome. J Biol Chem 278:311–318

    PubMed  CAS  Article  Google Scholar 

  • Siller-Jackson AJ, Burra S, Gu S, Xia X, Bonewald LF, Sprague E, Jiang JX (2008) Adaptation of connexin 43-hemichannel prostaglandin release to mechanical loading. J Biol Chem 283:26374–26382

    PubMed  CAS  Article  Google Scholar 

  • Simeckova P, Vondracek J, Andrysik Z, Zatloukalova J, Krcmar P, Kozubik A, Machala M (2009) The 2,2′,4,4′,5,5′-hexachlorobiphenyl-enhanced degradation of connexin 43 involves both proteasomal and lysosomal activities. Toxicol Sci 107:9–18

    PubMed  CAS  Article  Google Scholar 

  • Sirnes S, Leithe E, Rivedal E (2008) The detergent resistance of connexin43 is lost upon TPA or EGF treatment and is an early step in gap junction endocytosis. Biochem Biophys Res Commun 373:597–601

    PubMed  CAS  Article  Google Scholar 

  • Sirnes S, Kjenseth A, Leithe E, Rivedal E (2009) Interplay between PKC and the MAP kinase pathway in connexin43 phosphorylation and inhibition of gap junction intercellular communication. Biochem Biophys Res Commun 382:41–45

    PubMed  CAS  Article  Google Scholar 

  • Smith JH, Green CR, Peters NS, Rothery S, Severs NJ (1991) Altered patterns of gap junction distribution in ischemic heart disease. An immunohistochemical study of human myocardium using laser scanning confocal microscopy. Am J Pathol 139:801–821

    PubMed  CAS  Google Scholar 

  • Smith MH, Ploegh HL, Weissman JS (2011) Road to ruin: targeting proteins for degradation in the endoplasmic reticulum. Science 334:1086–1090

    PubMed  CAS  Article  Google Scholar 

  • Solan JL, Lampe PD (2005) Connexin phosphorylation as a regulatory event linked to gap junction channel assembly. Biochim Biophys Acta 1711:154–163

    PubMed  CAS  Article  Google Scholar 

  • Solan JL, Lampe PD (2007) Key connexin 43 phosphorylation events regulate the gap junction life cycle. J Membr Biol 217:35–41

    PubMed  CAS  Article  Google Scholar 

  • Solan JL, Lampe PD (2009) Connexin43 phosphorylation: structural changes and biological effects. Biochem J 419:261–272

    PubMed  CAS  Article  Google Scholar 

  • Srinivas M, Calderón DP, Kronengold J, Verselis VK (2006) Regulation of connexin hemichannels by monovalent cations. J Gen Physiol 127:67–75

    PubMed  CAS  Article  Google Scholar 

  • Stout C, Goodenough DA, Paul DL (2004) Connexins: functions without junctions. Curr Opin Cell Biol 16:507–512

    PubMed  CAS  Article  Google Scholar 

  • Su V, Lau AF (2009) Ubiquitin-like and ubiquitin-associated domain proteins: significance in proteasomal degradation. Cell Mol Life Sci 66:2819–2833

    PubMed  CAS  Article  Google Scholar 

  • Su V, Lau AF (2012) Ubiquitination, intracellular trafficking, and degradation of connexins. Arch Biochem Biophys 524:16–22

    PubMed  CAS  Article  Google Scholar 

  • Su V, Nakagawa R, Koval M, Lau AF (2010) Ubiquitin-independent proteasomal degradation of endoplasmic reticulum–localized connexin43 mediated by CIP75. J Biol Chem 285:40979–40990

    PubMed  CAS  Article  Google Scholar 

  • Thomas MA, Zosso N, Scerri I, Demaurex N, Chanson M, Staub O (2003) A tyrosine-based sorting signal is involved in connexin43 stability and gap junction turnover. J Cell Sci 116:2213–2222

    PubMed  CAS  Article  Google Scholar 

  • van Veen AA, van Rijen HV, Opthof T (2001) Cardiac gap junction channels: modulation of expression and channel properties. Cardiovasc Res 51:217–229

    PubMed  Article  Google Scholar 

  • VanSlyke JK, Musil LS (2002) Dislocation and degradation from the ER are regulated by cytosolic stress. J Cell Biol 157:381–394

    PubMed  CAS  Article  Google Scholar 

  • VanSlyke JK, Musil LS (2003) Degradation of connexins from the plasma membrane is regulated by inhibitors of protein synthesis. Cell Commun Adhes 10:329–333

    PubMed  CAS  Google Scholar 

  • VanSlyke JK, Musil LS (2005) Cytosolic stress reduces degradation of connexin43 internalized from the cell surface and enhances gap junction formation and function. Mol Biol Cell 16:5247–5257

    PubMed  CAS  Article  Google Scholar 

  • VanSlyke JK, Deschenes SM, Musil LS (2000) Intracellular transport, assembly, and degradation of wild-type and disease-linked mutant gap junction proteins. Mol Biol Cell 11:1933–1946

    PubMed  CAS  Google Scholar 

  • Vinken M, Vanhaecke T, Papeleu P, Snykers S, Henkens T, Rogiers V (2006) Connexins and their channels in cell growth and cell death. Cell Signal 18:592–600

    PubMed  CAS  Article  Google Scholar 

  • Voges D, Zwickl P, Baumeister W (1999) The 26S proteasome: a molecular machine designed for controlled proteolysis. Annu Rev Biochem 68:1015–1068

    PubMed  CAS  Article  Google Scholar 

  • Wei CJ, Xu X, Lo CW (2004) Connexins and cell signaling in development and disease. Annu Rev Cell Dev Biol 20:811–838

    PubMed  CAS  Article  Google Scholar 

  • White TW, Paul DL (1999) Genetic diseases and gene knockouts reveal diverse connexin functions. Annu Rev Physiol 61:283–310

    PubMed  CAS  Article  Google Scholar 

  • Xie H, Laird DW, Chang TH, Hu VW (1997) A mitosis-specific phosphorylation of the gap junction protein connexin43 in human vascular cells: biochemical characterization and localization. J Cell Biol 137:203–210

    PubMed  CAS  Article  Google Scholar 

  • Yang Z, Klionsky DJ (2009) An overview of the molecular mechanism of autophagy. Curr Top Microbiol Immunol 335:1–32

    PubMed  CAS  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by awards from the American Heart Association (11POST5460028, to V.S.), the Hawaii Community Foundation (11ADVC-49235, to V.S. and A.F.L.) and the National Cancer Institute, National Institutes of Health (CA052098-18, to A.F.L.).

Author information

Affiliations

  1. Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, 651 Ilalo Street, BSB 222, Honolulu, HI, 96813, USA

    Vivian Su, Kimberly Cochrane & Alan F. Lau

  2. Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI, 96813, USA

    Kimberly Cochrane & Alan F. Lau

Authors
  1. Vivian Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kimberly Cochrane
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alan F. Lau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vivian Su.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Su, V., Cochrane, K. & Lau, A.F. Degradation of Connexins Through the Proteasomal, Endolysosomal and Phagolysosomal Pathways. J Membrane Biol 245, 389–400 (2012). https://doi.org/10.1007/s00232-012-9461-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00232-012-9461-3

Keywords

  • Connexin
  • Degradation
  • Proteasome
  • Lysosome
  • Autophagy