Deceiving the gatekeepers: virus modulation of gap junctions

SUMMARYGap junctions (GJs) are specialized intercellular channels that mediate the direct exchange of ions, metabolites, and signaling molecules between adjacent cells, playing essential roles in tissue homeostasis and immune coordination. Their function is tightly controlled by connexin isoform composition, trafficking and turnover, and post-translational modifications, particularly phosphorylation and ubiquitination. This review synthesizes current knowledge on the diverse strategies employed by DNA and RNA viruses, including members of the <i>Herpesviridae</i>, <i>Adenoviridae, Papillomaviridae</i>, <i>Polyomaviridae</i>, <i>Retroviridae</i>, <i>Flaviviridae</i>, <i>Coronaviridae, Orthomyxoviridae, Bornaviridae, Peribunyaviridae,</i> and <i>Picornaviridae</i> families, to modulate gap junctional intercellular communication (GJIC) and the constituent connexin proteins. We highlight mechanisms such as phosphorylation-induced GJ closure and degradation, subcellular mislocalization, and transcriptional and post-transcriptional regulation of connexin expression. Viral modulation of GJIC serves a variety of purposes, including promoting viral spread, suppressing innate immune responses mediated by the cGAMP/STING pathway, and facilitating oncogenic transformation. Downregulation and/or selective reprogramming of GJIC during viral transformation mirrors changes seen in non-viral cancers, indicating that GJIC manipulation represents a shared mechanism underpinning both viral and non-viral cellular transformation in solid tumors. By integrating findings across diverse virus families, this review underscores GJIC modulation as a central virus-host interaction axis and identifies potential therapeutic targets for modulating GJIC in viral infections.