The TSG101 protein binds to connexins and is involved in connexin degradation

Auth, Tanja; Schlüter, Sharazad; Urschel, Stephanie; Kussmann, Petra; Sonntag, Stephan; Höher, Thorsten; Kreuzberg, Maria M.; Dobrowolski, Radoslaw; Willecke, Klaus

doi:10.1016/j.yexcr.2008.12.025

Cited by 39 publications

(30 citation statements)

References 51 publications

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“…While the present work was in progress, it was reported that Tsg101 binds to Cx31, Cx43 and Cx45 (Auth et al, 2009). It was also suggested that Tsg101 is involved in constitutive degradation of Cx43 and Cx45, but not Cx31.…”

Section: Discussionmentioning

confidence: 60%

Ubiquitylation of the gap junction protein connexin-43 signals its trafficking from early endosomes to lysosomes in a process mediated by Hrs and Tsg101

Leithe

Kjenseth

Sirnes

et al. 2009

Journal of Cell Science

128

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Gap junctions are dynamic plasma membrane domains, and their protein constituents, the connexins, have a high turnover rate in most tissue types. However, the molecular mechanisms involved in degradation of gap junctions have remained largely unknown. Here, we show that ubiquitin is strongly relocalized to connexin-43 (Cx43; also known as Gja1) gap junction plaques in response to activation of protein kinase C. Cx43 remained ubiquitylated during its transition to a Triton X-100-soluble state and along its trafficking to early endosomes. Following internalization, Cx43 partly colocalized with the ubiquitin-binding proteins Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate; also known as Hgs) and Tsg101 (tumor susceptibility gene 101). Depletion of Hrs or Tsg101 by small interfering RNA abrogated trafficking of Cx43 from early endosomes to lysosomes. Under these conditions, Cx43 was able to undergo dephosphorylation and deubiquitylation, locate to the plasma membrane and form functional gap junctions. Simultaneous depletion of Hrs and Tsg101 caused accumulation of a phosphorylated and ubiquitylated subpopulation of Cx43 in early endosomes and in hybrid organelles between partly degraded annular gap junctions and endosomes. Collectively, these data reveal a central role of early endosomes in sorting of ubiquitylated Cx43, and identify Hrs and Tsg101 as crucial regulators of trafficking of Cx43 to lysosomes.

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Section: Discussionmentioning

confidence: 60%

Ubiquitylation of the gap junction protein connexin-43 signals its trafficking from early endosomes to lysosomes in a process mediated by Hrs and Tsg101

Leithe

Kjenseth

Sirnes

et al. 2009

Journal of Cell Science

128

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“…Virally ubiquitinated class I MHC is degraded via the ESCRTs (Hewitt et al , 2002). The gap junction protein connexin-43 undergoes regulated turnover that is ESCRT-dependent (Auth et al , 2009; Worsdorfer et al , 2008). In yeast, the GPCRs Ste2 (Odorizzi et al , 1998) and Ste3 (Piper et al , 1995) are substrates of the ESCRT pathway.…”

Section: Cellular Functions Of the Escrtsmentioning

confidence: 99%

The ESCRT complexes

Hurley

2010

Critical Reviews in Biochemistry and Molecular Biology

304

296

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The ESCRT machinery consists of the peripheral membrane protein complexes, ESCRT-0, -I, -II, -III, and Vps4-Vta1, and the ALIX homodimer. The ESCRT system is required for degradation of unneeded or dangerous plasma membrane proteins; biogenesis of the lysosome and the yeast vacuole; the budding of most membrane enveloped viruses; the membrane abscission step in cytokinesis; macroautophagy; and several other processes. From their initial discovery in 2001-2002, the literature on ESCRTs has grown exponentially. This review will describe the structure and function of the six complexes noted above and summarizes current knowledge of their mechanistic roles in cellular pathways and in disease.

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“…Ubiquitylation of Cx43 has been suggested to be involved in regulating gap junction endocytosis by recruiting the ubiquitinbinding protein Eps15 (EGF receptor pathway substrate 15) to gap junction plaques (Girão et al, 2009). Ubiquitylation has also been implicated in controlling the trafficking of Cx43 from early endosomes to lysosomes, in a process involving the ubiquitin-binding proteins Hrs (hepatocyte-growth-factorregulated tyrosine kinase substrate) and Tsg101 (tumor susceptibility gene 101) (Auth et al, 2009;Leithe et al, 2009;Malerød et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Smad ubiquitination regulatory factor-2 controls gap junction intercellular communication by modulating endocytosis and degradation of connexin43

Fykerud

Kjenseth

Schink

et al. 2012

Journal of Cell Science

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SummaryGap junctions consist of arrays of intercellular channels that enable adjacent cells to communicate both electrically and metabolically. Gap junction channels are made of a family of integral membrane proteins called connexins, of which the best-studied member is connexin43. Gap junctions are dynamic plasma membrane domains, and connexin43 has a high turnover rate in most tissue types. However, the mechanisms involved in the regulation of connexin43 endocytosis and transport to lysosomes are still poorly understood. Here, we demonstrate by live-cell imaging analysis that treatment of cells with 12-O-tetradecanoylphorbol 13-acetate (TPA) induces endocytosis of subdomains of connexin43 gap junctions. The internalized, connexin43-enriched vesicles were found to fuse with early endosomes, which was followed by transport of connexin43 to the lumen of early endosomes. The HECT E3 ubiquitin ligase smad ubiquitination regulatory factor-2 (Smurf2) was found to be recruited to connexin43 gap junctions in response to TPA treatment. Depletion of Smurf2 by small interfering RNA resulted in enhanced levels of connexin43 gap junctions between adjacent cells and increased gap junction intercellular communication. Smurf2 depletion also counteracted the TPA-induced endocytosis and degradation of connexin43. Collectively, these data identify Smurf2 as a novel regulator of connexin43 gap junctions.

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The TSG101 protein binds to connexins and is involved in connexin degradation

Cited by 39 publications

References 51 publications

Ubiquitylation of the gap junction protein connexin-43 signals its trafficking from early endosomes to lysosomes in a process mediated by Hrs and Tsg101

Ubiquitylation of the gap junction protein connexin-43 signals its trafficking from early endosomes to lysosomes in a process mediated by Hrs and Tsg101

The ESCRT complexes

Smad ubiquitination regulatory factor-2 controls gap junction intercellular communication by modulating endocytosis and degradation of connexin43

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