Work

The actin-binding protein drebrin interacts with the respiratory syncytial virus matrix protein and promotes virus particle release

Year: 2026

Type: preprint

Abstract: ABSTRACT Respiratory syncytial virus (RSV) is an enveloped virus that assembles and buds at the plasma membrane, producing filamentous infectious particles. Unlike many other enveloped viruses, a substantial fraction of RSV virions remains associated with the surface of infected cells, limiting our understanding of the membrane-scission mechanisms responsible for particle release. Here, we identified the actin-binding protein drebrin as a cellular interactor of the RSV matrix (M) protein, both in vitro and in infected cells. We demonstrated that RSV infection induces the relocalization of drebrin to actin-rich structures at the cell periphery associated with viral filaments. Using a Transwell-based assay to quantify infectious particles release without mechanically perturbing cells, we confirmed that RSV release is independent of the endosomal sorting complex required for transport (ESCRT) pathway and showed that drebrin depletion reduced RSV release, whereas drebrin overexpression enhanced it. Since drebrin depletion did not significantly affect overall infectious virus production, our results suggest that drebrin may act during the final step leading to membrane scission and RSV particle release. Finally, proteomics analysis identified Transmembrane 9 superfamily member 2 (TM9SF2) as a drebrin-associated protein specifically during infection. TM9SF2 depletion reduced RSV particle release and impaired the RSV-induced relocalization of drebrin to the plasma membrane. Together, these findings identify drebrin and TM9SF2 as host factors regulating RSV release and support a model in which TM9SF2 promotes the recruitment of drebrin to viral budding sites. IMPORTANCE Respiratory syncytial virus is a major cause of respiratory disease, especially in infants and older adults. To spread, the virus must produce new particles and release them from infected cells, but how this final step occurs remains poorly understood. We identified one cellular protein, drebrin that interacts with the matrix viral protein and helps newly formed virus particles leave infected cells. Drebrin moves to sites where virus particles form and is needed for efficient release of infectious particles. We also found that the cellular protein, transmembrane 9 superfamily member 2, is required for drebrin recruitment to the cell periphery, near the sites of release. Our results suggest that drebrin and transmembrane 9 superfamily member 2 act late in the release process, helping particles separate from the cell surface.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.10.05.756730