EPAC2-associated Junction Plakoglobin and its role in Respiratory Syncytial Virus Infection 9151

Description Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in infants, young children, and immunocompromised individuals. Despite the availability of an FDA-approved monoclonal antibody treatment, unmet therapeutic needs remain, necessitating further studies on disease mechanisms to identify new treatment strategies. Exchange proteins directly activated by cAMP (EPAC) have recently emerged as critical regulators of viral infections. Our previous researh demonstrated that EPAC isoform 2 (EPAC2) significantly influences RSV replication and innate immune responses. However, the mechanisms undrelying EPAC2’s role in RSV infection remain unclear. This study explored EPAC2-mediated signaling by idenfying EPAC2-bound proteins during RSV infection. We discovered that junction plakoglobin (JUP), a protein associated with EPAC2 in uninfected cells, showed increased binding to EPAC2 by RSV infection. Functional analyses revealed that JUP is crucial for RSV replication. JUP downregulation led to reduce production of infectious particles, likely by targeting RSV fusion protein synthesis. Addtionally, JUP plays a role in replication-independent inflmaamtory regulation. Overall, these results suggest a cooperative role of EPAC2 and JUP in controlling RSV replication and modulating the viral fusion and invasion process, offering new insights into RSV pathogenesis and potential therapeutic targets. Funding Sources This work was supported by grants from the US National Institutes of Health (NIH) R21 AI166543, R61 AG075725, ERP-1252718 from American Lung Association to X.