Beyond the Capsid: How Can Post-Translational Modifications Modulate the Multifunctionality of the Orthoflavivirus Capsid Protein?

The orthoflavivirus capsid protein (C) is a multifunctional protein that plays essential roles throughout the viral life cycle. Beyond viral RNA encapsidation and nucleocapsid assembly, it associates with lipid droplets, interacts with host proteins, and translocates to the nucleus, although its nuclear functions remain poorly understood. How these diverse activities are coordinated remains an open question. Post-translational modifications (PTMs), key regulators of protein function, have emerged as critical modulators of viral replication in many RNA viruses. However, their occurrence and functional significance in orthoflavivirus C proteins remain largely unexplored. Here, we review current evidence on PTMs in orthoflavivirus C proteins and integrate insights into their roles in other RNA viruses to propose mechanisms by which PTMs may regulate capsid function. To com-plement this review, we performed a comparative in silico analysis of predicted PTM sites in the C proteins of dengue, Zika, West Nile, and Japanese encephalitis viruses. By inte-grating PTM predictions with experimentally validated modification sites, residue con-servation, and structural mapping, we identified conserved regulatory hotspots that rep-resent promising targets for future experimental validation. Together, these findings high-light PTMs as an underexplored regulatory level of orthoflavivirus capsid biology and provide a framework for future mechanistic investigations.