Dynamic UTR Usage Regulates Alternative Translation to Modulate Gap Junction Formation during Stress and Aging

Academic Article

Abstract

  • Connexin43 (Cx43; gene name GJA1) is the most ubiquitously expressed gap junction protein, and understanding of its regulation largely falls under transcription and post-translational modification. In addition to Cx43, Gja1 mRNA encodes internally translated isoforms regulating gap junction formation, whose expression is modulated by TGF-β. Here, using RLM-RACE, we identify distinct Gja1 transcripts differing only in 5′ UTR length, of which two are upregulated during TGF-β exposure and hypoxia. Introduction of these transcripts into Gja1−/− cells phenocopies the response of Gja1 to TGF-β with reduced internal translation initiation. Inhibiting pathways downstream of TGF-β selectively regulates levels of Gja1 transcript isoforms and translation products. Reporter assays reveal enhanced translation of full-length Cx43 from shorter Gja1 5′ UTR isoforms. We also observe a correlation among UTR selection, translation, and reduced gap junction formation in aged heart tissue. These data elucidate a relationship between transcript isoform expression and translation initiation regulating intercellular communication.
  • Authors

    Published In

  • Cell Reports  Journal
  • Digital Object Identifier (doi)

    Author List

  • Zeitz MJ; Calhoun PJ; James CC; Taetzsch T; George KK; Robel S; Valdez G; Smyth JW
  • Start Page

  • 2737
  • End Page

  • 2747.e5
  • Volume

  • 27
  • Issue

  • 9