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Adenovirus targets transcriptional and posttranslational mechanisms to limit gap junction function.
Calhoun, Patrick J; Phan, Allen V; Taylor, Jordan D; James, Carissa C; Padget, Rachel L; Zeitz, Michael J; Smyth, James W.
Affiliation
  • Calhoun PJ; Fralin Biomedical Research Institute at VTC, Roanoke, VA, USA.
  • Phan AV; Department of Biological Sciences, Virginia Tech, Blacksburg, VA, USA.
  • Taylor JD; Virginia Tech Carilion School of Medicine, Roanoke, VA, USA.
  • James CC; Virginia Tech Carilion School of Medicine, Roanoke, VA, USA.
  • Padget RL; Fralin Biomedical Research Institute at VTC, Roanoke, VA, USA.
  • Zeitz MJ; Graduate Program in Translational Biology, Medicine, and Health, Virginia Tech, Blacksburg, VA, USA.
  • Smyth JW; Fralin Biomedical Research Institute at VTC, Roanoke, VA, USA.
FASEB J ; 34(7): 9694-9712, 2020 07.
Article in En | MEDLINE | ID: mdl-32485054
Adenoviruses are responsible for a spectrum of pathogenesis including viral myocarditis. The gap junction protein connexin43 (Cx43, gene name GJA1) facilitates rapid propagation of action potentials necessary for each heartbeat. Gap junctions also propagate innate and adaptive antiviral immune responses, but how viruses may target these structures is not understood. Given this immunological role of Cx43, we hypothesized that gap junctions would be targeted during adenovirus type 5 (Ad5) infection. We find reduced Cx43 protein levels due to decreased GJA1 mRNA transcripts dependent upon ß-catenin transcriptional activity during Ad5 infection, with early viral protein E4orf1 sufficient to induce ß-catenin phosphorylation. Loss of gap junction function occurs prior to reduced Cx43 protein levels with Ad5 infection rapidly inducing Cx43 phosphorylation events consistent with altered gap junction conductance. Direct Cx43 interaction with ZO-1 plays a critical role in gap junction regulation. We find loss of Cx43/ZO-1 complexing during Ad5 infection by co-immunoprecipitation and complementary studies in human induced pluripotent stem cell derived-cardiomyocytes reveal Cx43 gap junction remodeling by reduced ZO-1 complexing. These findings reveal specific targeting of gap junction function by Ad5 leading to loss of intercellular communication which would contribute to dangerous pathological states including arrhythmias in infected hearts.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Transcription, Genetic / Cell Communication / Adenoviridae / Gap Junctions / Connexin 43 / Adenoviridae Infections / Myocytes, Cardiac Limits: Humans Language: En Journal: FASEB J Journal subject: BIOLOGIA / FISIOLOGIA Year: 2020 Document type: Article Affiliation country: Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Transcription, Genetic / Cell Communication / Adenoviridae / Gap Junctions / Connexin 43 / Adenoviridae Infections / Myocytes, Cardiac Limits: Humans Language: En Journal: FASEB J Journal subject: BIOLOGIA / FISIOLOGIA Year: 2020 Document type: Article Affiliation country: Country of publication: