New directions in the multifunctionality of RNA viruses: insights from the rabies virus P-protein

RNA viruses have compact genomes that typically encode only a few proteins, but these viruses orchestrate complex replication cycles while concurrently exercising control over multiple aspects of the biology of the infected host cell, including the evasion of antiviral responses. Central to this functional diversity is the evolution of multifunctional proteins, which integrate diverse roles in replication and host subversion through structural, regulatory, and spatial versatility. The rabies virus P-protein exemplifies these principles. In addition to serving as an essential cofactor and chaperone in viral transcription and replication, the P-protein also antagonizes type I interferon responses, modulates intranuclear processes, and targets multiple host membrane-less organelles via liquid-liquid phase separation. These diverse functions are mediated by a combination of mechanisms, including expression as multiple isoforms, modular domain architecture, intrinsic disorder, dynamic subcellular trafficking, post-translational modifications, conformational plasticity, and RNA binding. In this review, we discuss established and recently emerging mechanisms underlying P-protein multifunctionality, which is likely to provide a model for understanding the multifunctionality of other viral, and likely cellular proteins. We also highlight how similar strategies are employed across RNA viruses to overcome genomic constraints, and discuss how these mechanisms may represent promising targets for future antiviral interventions.