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Cell Rep. 2019 May 28;27(9):2737-2747.e5. doi: 10.1016/j.celrep.2019.04.114.

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

Author information

1
Fralin Biomedical Research Institute, Roanoke, VA 24016, USA.
2
Fralin Biomedical Research Institute, Roanoke, VA 24016, USA; Department of Biological Sciences, Virginia State University and Polytechnic Institute, Blacksburg, VA 24060, USA.
3
Fralin Biomedical Research Institute, Roanoke, VA 24016, USA; Graduate Program in Translational Biology, Medicine, and Health, Virginia State University and Polytechnic Institute, Blacksburg, VA 24060, USA.
4
Fralin Biomedical Research Institute, Roanoke, VA 24016, USA; Department of Biological Sciences, Virginia State University and Polytechnic Institute, Blacksburg, VA 24060, USA; Virginia Tech Carilion School of Medicine, Roanoke, VA 24016, USA; School of Neuroscience, Virginia State University and Polytechnic Institute, Blacksburg, VA 24060, USA.
5
Fralin Biomedical Research Institute, Roanoke, VA 24016, USA; Department of Biological Sciences, Virginia State University and Polytechnic Institute, Blacksburg, VA 24060, USA; Virginia Tech Carilion School of Medicine, Roanoke, VA 24016, USA.
6
Fralin Biomedical Research Institute, Roanoke, VA 24016, USA; Department of Biological Sciences, Virginia State University and Polytechnic Institute, Blacksburg, VA 24060, USA; Virginia Tech Carilion School of Medicine, Roanoke, VA 24016, USA. Electronic address: smythj@vtc.vt.edu.

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.

KEYWORDS:

TGF-β; UTR; aging; connexin; gap junction; mRNA; translation

PMID:
31141695
DOI:
10.1016/j.celrep.2019.04.114
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