Journal
CELL REPORTS
Volume 27, Issue 9, Pages 2737-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.04.114
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Funding
- NIH NHLBI R01 grant [HL132236]
- NHLBI F31 grant [HL140909]
- NIA R01 grant [AG055545]
- NINDS R21 grant [NS107941, NS106313]
- NINDS R01 grant [NS105807]
- American Heart Association [18PRE33960573]
- NIH
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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-beta. Here, using RLM-RACE, we identify distinct Gja1 transcripts differing only in 5' UTR length, of which two are upregulated during TGF-beta exposure and hypoxia. Introduction of these transcripts into Gja1-/- cells phenocopies the response of Gja1 to TGF-beta with reduced internal translation initiation. Inhibiting pathways downstream of TGF-beta 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.
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