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

## TL;DR

This study explores how EPAC2 and junction plakoglobin interact during RSV infection, revealing a potential role in virus replication and immune response.

## Contribution

The novel contribution is identifying junction plakoglobin as an EPAC2-interacting protein critical for RSV replication and immune response.

## Key findings

- Junction plakoglobin interacts with EPAC2 and this interaction increases during RSV infection.
- Reducing junction plakoglobin decreases RSV particle production by impairing viral budding and gene transcription.
- Junction plakoglobin is essential for an effective immune response to RSV.

## Abstract

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 (EPAC) have recently emerged as key regulators in various viral infections. Our previous work identified EPAC isoform 2 (EPAC2) as a critical factor in RSV replication and host innate immune responses. However, the molecular mechanisms underlying EPAC2’s role in RSV infection remain unclear. In this study, we investigated EPAC2-mediated RSV infection by identifying EPAC2-interacting proteins. Proteomics and immunoprecipitation analyses revealed that junction plakoglobin (JUP) interacts with EPAC2 in both mock- and RSV-infected cells, with this interaction notably enhanced during RSV infection. To determine JUP’s role in RSV infection, we compared viral replication in JUP-deficient and control cells. JUP downregulation significantly reduced the production of infectious RSV particles, likely by impairing viral budding and viral gene transcription. Moreover, our findings indicate that JUP is essential for an effective cellular immune response to RSV infection. Together, these results suggest that EPAC2 and JUP may cooperatively regulate RSV replication and dissemination.