The Impact of EPAC2-Associated Junction Plakoglobin on Respiratory Syncytial Virus Infection

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections in infants, young children, and immunocompromised individuals. Currently, FDA-approved monoclonal antibody therapies are limited to infants and young children with severe RSV disease. As a result, there is an urgent need for comprehensive studies of RSV pathogenesis to support the development of new therapeutic strategies. Exchange proteins directly activated by cAMP (<i>EPAC</i>) have recently emerged as key regulators in various viral infections. Our previous work identified EPAC isoform 2 (<i>EPAC2</i>) as a critical factor in RSV replication and host innate immune responses. However, the molecular mechanisms underlying <i>EPAC2</i>'s role in RSV infection remain unclear. In this study, we investigated <i>EPAC2</i>-mediated RSV infection by identifying <i>EPAC2</i>-interacting proteins. Proteomics and immunoprecipitation analyses revealed that junction plakoglobin (<i>JUP</i>) interacts with <i>EPAC2</i> in both mock- and RSV-infected cells, with this interaction notably enhanced during RSV infection. To determine <i>JUP</i>'s role in RSV infection, we compared viral replication in <i>JUP</i>-deficient and control cells. <i>JUP</i> downregulation significantly reduced the production of infectious RSV particles, likely by impairing viral budding and viral gene transcription. Moreover, our findings indicate that <i>JUP</i> is essential for an effective cellular immune response to RSV infection. Together, these results suggest that <i>EPAC2</i> and <i>JUP</i> may cooperatively regulate RSV replication and dissemination.