A scaffold for success: The many phases of herpesvirus capsid assembly

Viruses are masters of cellular reorganization and self-assembly processes, including the formation of a protein capsid that protects and traffics the viral genome. One example are Herpesviruses, a group of enveloped, double-stranded DNA viruses that establish lifelong, latent infections in a wide range of hosts, including humans. These large viruses assemble an ~125-nm capsid in the nucleus through a coordinated series of steps that culminates in packaging of DNA genomes up to 250 kilobases in length and nuclear egress to the cytoplasm. Despite more than three decades of study, the precise mechanisms underlying herpesvirus capsid assembly remain unclear. Central to this process is the Scaffold protein, which supports capsid growth and ensures proper capsid geometry. Here, we revisit evidence suggesting that the Scaffold functions as more than a structural support. We highlight prior observations indicating that it may promote the formation of nuclear capsid assembly sites through self-interactions. By integrating these findings with recent structural studies, we identify key gaps in our understanding of herpesvirus capsid assembly and areas that warrant renewed investigation.