Adenovirus targets transcriptional and posttranslational mechanisms to limit gap junction function

• DOI: 10.1096/fj.202000667r
• Publication Date: 2020-07-27T14:37:08Z
• Authors: Patrick J. Calhoun; Allen V. Phan; Jordan D. Taylor; Carissa C. James; Rachel L. Padget; Michael J. Zeitz; James W. Smyth
• Keywords: Immunoprecipitation

Adenoviruses are responsible for a spectrum of pathogenesis including viral myocarditis. The gap junction protein connexin43 (Cx43, gene name GJA1) facilitates rapid propagation action potentials necessary 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 Cx43, we hypothesized that would be targeted during adenovirus type 5 (Ad5) infection. We find reduced Cx43 levels due to decreased GJA1 mRNA transcripts dependent upon β-catenin transcriptional activity Ad5 infection, with early E4orf1 sufficient induce phosphorylation. Loss function occurs prior infection rapidly inducing phosphorylation events consistent altered conductance. Direct interaction ZO-1 plays critical in regulation. loss Cx43/ZO-1 complexing by co-immunoprecipitation complementary studies human induced pluripotent stem cell derived-cardiomyocytes reveal remodeling complexing. These findings specific targeting leading intercellular communication which contribute dangerous pathological states arrhythmias infected hearts.