Internal translation within Cx43 mRNA produces truncated isoforms, predominantly a 20 kDa isoform, that act as trafficking chaperones to autoregulate Cx43 gap junction formation.
Does internal translation of Cx43 isoforms regulate gap junction formation and trafficking in the heart?
Internal translation of Cx43 mRNA produces truncated isoforms that autoregulate gap junction formation, offering a potential therapeutic target for restoring electrical coupling in failing and arrhythmogenic hearts.
During 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 cap-dependent 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.
Smyth et al. (Fri,) conducted a other in Heart failure / Arrhythmias. mTOR inhibition was evaluated on Cx43 trafficking and gap junction size. Internal translation within Cx43 mRNA produces truncated isoforms, predominantly a 20 kDa isoform, that act as trafficking chaperones to autoregulate Cx43 gap junction formation.