<i>Ec</i> CXCR4b influences RGNNV proliferation by interacting with the RGNNV capsid protein

Red-spotted grouper nervous necrosis virus (RGNNV) is the most prevalent genotype in Betanodavirus and infects numerous fish species in warm water environments. In the viral infectious life cycle, virus-receptor recognition and interactions play a crucial role. Nevertheless, the host interaction proteins involved in RGNNV infection are still not completely understood. Therefore, further research is required to identify additional host proteins involved in RGNNV invasion to refine our understanding of its pathogenic mechanisms. In this study, we identified <i>Epinephelus coioides</i> CXC chemokine receptor 4b (<i>Ec</i>CXCR4b) as RGNNV-CP interacting protein, and further analyses revealed that this interaction is of vital importance for RGNNV attachment and internalization. Additionally, <i>Ec</i>CXCR4b facilitates RGNNV entry into host cells via the clathrin-dependent endocytic mechanisms. These findings suggest that <i>Ec</i>CXCR4b serves as a critical host factor involved in RGNNV endocytosis, providing new insight into the intricate mechanisms underlying RGNNV entrance and useful prospective targets for antiviral medication development.