Rapid evolution of mammalian HERC6 and independent duplication of a chimeric HERC5/6 gene in rodents and bats suggest an overlooked role of HERCs in antiviral innate immunity

The antiviral innate immunity in mammals has evolved very rapidly in response to pathogen selective pressure. Studying the evolutionary diversification of mammalian antiviral defenses is of main importance to better understand our innate immune repertoire. The small HERC proteins are part of a multigene family including interferon-inducible antiviral effectors. Notably, HERC5 inhibits divergent viruses through the conjugation of ISG15 to diverse proteins-termed as ISGylation. Though HERC6 is the most closely-related protein of HERC5, it lacks the ISGylation function in humans. Interestingly, HERC6 is the main E3-ligase of ISG15 in mice, suggesting adaptive changes in HERC6 with implications in the innate immunity. Therefore, HERC5 and HERC6 have probably diversified through complex evolutionary history in mammals, and such characterization would require an extensive survey of mammalian evolution. Here, we performed mammalian-wide and lineage-specific phylogenetic and genomic analyses of HERC5 and HERC6. We used 83 orthologous sequences from bats, rodents, primates, artiodactyls and carnivores – the top five representative groups of mammalian evolution and the main hosts of viral diversity. We found that mammalian HERC5 has been under weak and differential positive selection in mammals, with only primate HERC5 showing evidences of pathogen-driven selection. In contrast, HERC6 has been under strong and recurrent adaptive evolution in mammals, suggesting past genetic arms-races with viral pathogens. Importantly, we found accelerated evolution in the HERC6 spacer domain, suggesting that it might be a pathogen-mammal interface, targeting a viral protein and/or being the target of virus antagonists. Finally, we identified a HERC5/6 chimeric gene that arose from independent duplication in rodent and bat lineages and encodes for a conserved HERC5 N-terminal domain and divergent HERC6 spacer and HECT domains. This duplicated chimeric gene highlights adaptations that potentially contribute to rodent and bat antiviral innate immunity. Altogether, we found major genetic innovations in mammalian HERC5 and HERC6. Our findings open new research avenues on the functions of HERC6 and HERC5/6 in mammals, and on their implication in antiviral innate immunity.