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Autoregulation of Connexin43 Gap Junction Formation by Internally Translated Isoforms

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dc.contributor.authorSmyth, James W.en
dc.contributor.authorShaw, Robin M.en
dc.date.accessioned2019-06-03T21:02:49Zen
dc.date.available2019-06-03T21:02:49Zen
dc.date.issued2013en
dc.description.abstractDuring each heartbeat, intercellular electrical coupling via connexin43 (Cx43) gap junctions enables synchronous cardiac contraction. In failing hearts, impaired Cx43 trafficking reduces gap junction coupling, resulting in arrhythmias. Here we report that internal translation within Cx43 (GJA1) mRNA occurs, resulting in truncated isoforms that autoregulate Cx43 trafficking. We find that at least four truncated Cx43 isoforms occur in the human heart, with a 20 kDa isoform predominating. In-frame AUG codons within GJA1 mRNA are the translation initiation sites and their ablation arrests trafficking of full-length Cx43. The 20 kDa isoform is sufficient to rescue this trafficking defect in trans, suggesting it as a trafficking chaperone for Cx43. Limiting capdependent translation through inhibition of mTOR enhances truncated isoform expression, increasing Cx43 gap junction size. The results suggest that internal translation is a mechanism of membrane protein autoregulation and a potent target for therapies aimed at restoring normal electrical coupling in diseased hearts.en
dc.description.sponsorshipThis work was supported in part by the NIH (grant HL094414 to R.M.S.) and the American Heart Association (Scientist Development Grant SDG3420042 to J.W.S. and Grant in Aid GIA7030001 to R.M.S.).en
dc.format.extent8 pagesen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1016/j.celrep.2013.10.009en
dc.identifier.urihttp://hdl.handle.net/10919/89695en
dc.identifier.volume5en
dc.language.isoenen
dc.publisherCellen
dc.rightsCreative Commons Attribution-NonCommercial-No Derivatives 4.0en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0en
dc.titleAutoregulation of Connexin43 Gap Junction Formation by Internally Translated Isoformsen
dc.title.serialCell Reportsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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