Virion-wide interactome mapping of HSV-1 reveals maturation-dependent remodeling and convergent organization of herpesvirus tegument networks

This study presents a comprehensive spatial and quantitative protein proximity map of herpes simplex virus 1 (HSV-1) virions, generated by combining cross-linking mass spectrometry with quantitative proteomics. By integrating this virion map with existing intracellular interaction data, the authors show that virion maturation acts as a selective filter, transforming broad virus-host associations into an organized particle network. This process depletes biosynthetic and nuclear components while enriching interactions involved in tegument organization and envelope acquisition, centered around the tegument protein UL49.

Comparative analysis with analogous maps from human cytomegalovirus (HCMV) revealed that HSV-1 UL49 and HCMV UL32 are functionally equivalent network hubs despite lacking sequence or evolutionary relatedness. Both hubs converge on shared phosphoregulatory host factors, short linear interaction motifs, and liquid-liquid phase separation, pointing to conserved organizational principles underlying herpesvirus particle assembly. At the virion surface, the host complement regulator CD59 was found to protect particles from complement-mediated inactivation.

The findings reveal how conserved architectural principles shape virus-specific virion interaction networks during herpesvirus maturation, providing a resource for understanding herpesvirus assembly and potential targets for antiviral intervention.