In a groundbreaking study published in Nature Communications, Australian scientists have unveiled the sophisticated tactics employed by the rabies virus to manipulate host cells, despite possessing an extremely limited genetic toolkit. This work, led by teams at Monash University and the University of Melbourne, sheds light on the remarkable multifunctionality of a single viral protein, known as the P protein, revealing mechanisms that could revolutionize our understanding of viral biology and potentially pave the way for novel antiviral therapies.
Viruses are renowned for their ability to exert profound impacts on their hosts with minimalist genomes. The rabies virus, for instance, encodes only five proteins, a stark contrast to the roughly 20,000 proteins produced by human cells. This disparity has long puzzled virologists: how can so few proteins orchestrate the takeover of complex cellular processes? The new research identifies dynamic conformational changes and RNA-binding capabilities as key strategies that enable viral proteins to function with extraordinary versatility.
Central to this discovery is the observation that the P protein can adopt multiple distinct shapes, or conformations, enabling it to interact with various cellular components in different contexts. This structural plasticity defies the traditional modular view of proteins as linear assemblies of domains, each with fixed functions. Instead, the rabies P protein’s domains exhibit context-dependent folding and interaction patterns, leading to emergent properties such as RNA binding, which had not been fully appreciated before.
RNA molecules within cells are not mere passive carriers of genetic information; they engage in intricate networks that regulate gene expression, immune responses, and the assembly of cellular machinery. The study reveals that the P protein’s ability to bind RNA is a critical factor underpinning its multifunctionality. By attaching to RNA, the protein can infiltrate and exploit membrane-less organelles—liquid-like compartments formed through phase separation—that coordinate essential cellular activities.
Phase separation, a physical phenomenon where biomolecules demix to form concentrated droplets within the cytoplasm or nucleus, is emerging as a fundamental organizing principle in cell biology. The rabies P protein’s capacity to toggle between different physical phases allows it to enter these specialized compartments, such as nucleoli, and manipulate cellular processes including protein synthesis, intracellular signaling, and immune evasion. This ability essentially transforms the infected cell into a highly efficient virus-producing factory.
Microscopic imaging using confocal microscopy has vividly demonstrated these interactions in human cells. The P protein forms liquid-like droplets inside the nucleus, localizing to nucleoli—key hubs of ribosome biogenesis—and associates with microtubules, the structural scaffold of the cell. Such spatial and functional targeting exemplifies the virus’s strategy to exploit existing cellular infrastructure for viral replication and assembly.
Beyond rabies, the findings have significant implications for other high-priority pathogens like Nipah and Ebola viruses. These pathogens also encode relatively few proteins but exhibit broad cellular control and immune modulation. It is plausible that they too leverage conformational adaptability and RNA-binding to hijack host cellular systems. Understanding these shared viral strategies could unlock broad-spectrum antiviral approaches that disrupt this functional versatility.
The study also challenges prevailing conceptual frameworks in virology, which often liken multifunctional viral proteins to train carriages—distinct modules each responsible for a single task. This research posits a more dynamic model in which protein shape-shifting and intra-domain interactions generate a repertoire of functions from a single polypeptide chain, highlighting a sophisticated biophysical and biochemical strategy.
This deeper understanding of how viral proteins manipulate the physical chemistry of the host cell environment opens new avenues for drug development. Targeting the conformational dynamics or RNA-binding interfaces of viral proteins may yield therapies that incapacitate their multifunctionality, thereby hampering viral replication and pathogenesis. This approach could complement existing antiviral strategies, which mostly focus on viral enzymes or entry mechanisms.
The multidisciplinary study brought together expertise from molecular virology, structural biology, and biophysics, leveraging cutting-edge techniques such as live-cell imaging, biophysical assays, and advanced microscopy. Collaborators included the Australian Synchrotron and several research institutions across Australia, underscoring the collaborative nature of this discovery.
Ultimately, this research elevates our comprehension of viral protein multifunctionality and illustrates a paradigm shift in how we conceptualize viral infection mechanisms. By revealing the interplay between protein conformation, RNA binding, and phase separation, it not only expands the fundamental biological understanding but also sets the stage for translational research aimed at combating some of the world’s deadliest viruses.
The insights gleaned from this work underscore the sophistication of viral evolution and the elegant simplicity with which viruses exploit cellular systems. Future studies will likely explore whether the principles uncovered here apply more broadly across viral families and how they might be targeted therapeutically to prevent or mitigate viral diseases.
Subject of Research: Cells
Article Title: Conformational dynamics, RNA binding, and phase separation regulate the multifunctionality of rabies virus P protein
News Publication Date: 5-Nov-2025
Web References:
https://www.nature.com/articles/s41467-025-65223-y
http://doi.org/10.1038/s41467-025-65223-y
References:
Rawlinson, S., Moseley, G., Gooley, P., et al. (2025). Conformational dynamics, RNA binding, and phase separation regulate the multifunctionality of rabies virus P protein. Nature Communications.
Image Credits:
Stephen Rawlinson, Monash University
Keywords: Human health, Diseases and disorders
Tags: antiviral therapy developmentdynamic conformational changes in proteinshost cell takeover mechanismsimpact of viruses on host organismsminimalistic viral genomesMonash University viral researchmultifunctionality of viral proteinsP protein structural plasticityrabies virus manipulation strategiesRNA-binding capabilities of virusesviral biology understandingvirology research advancements
