Rapid Evolution of HERC6 and Duplication of a Chimeric HERC5/6 Gene in Rodents and Bats Suggest an Overlooked Role of HERCs in Mammalian Immunity

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 HERC5 and HERC6, which have probably diversified through complex evolutionary history in mammals. Here, we performed mammalian-wide phylogenetic and genomic analyses of HERC5 and HERC6, using 83 orthologous sequences from bats, rodents, primates, artiodactyls, and carnivores—the top five representative groups of mammalian evolution. We found that 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 and widespread genetic arms-races with viral pathogens. Importantly, the rapid evolution of mammalian HERC6 spacer domain suggests that it might be a host-pathogen interface, targeting viral proteins 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 immunity. Our findings open new research avenues on the functions of HERC6 and HERC5/6 in mammals, and on their implication in antiviral innate immunity.

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.

HERC Ubiquitin Ligases in Cancer

HERC proteins are ubiquitin E3 ligases of the HECT family. The HERC subfamily is composed of six members classified by size into large (HERC1 and HERC2) and small (HERC3–HERC6). HERC family ubiquitin ligases regulate important cellular processes, such as neurodevelopment, DNA damage response, cell proliferation, cell migration, and immune responses. Accumulating evidence also shows that this family plays critical roles in cancer. In this review, we provide an integrated view of the role of these ligases in cancer, highlighting their bivalent functions as either oncogenes or tumor suppressors, depending on the tumor type. We include a discussion of both the molecular mechanisms involved and the potential therapeutic strategies.

The Emerging Roles of the HERC Ubiquitin Ligases in Cancer

Background: The HERC family contains six members from HERC1 to HERC6 that are featured with the HECT domains that exerts ubiquitin ligase activity and the RCC1-like domains that are involved in cell cycle regulation. Although identified as early as 1990s, their biological functions are extensively studied in recent years. More and more researches have demonstrated that the HERC ubiquitin ligases are widely engaged in carcinogenesis, however, there lacks a comprehensive and instructive analysis. Methods: The PubMed database was searched by keywords of individual HERC proteins (such as HERC4) and cancer. The emerging roles of HERC proteins in cancer and the specific mechanisms were collectively analyzed and discussed. Results: HERC proteins belong to the HECT domain-containing ubiquitin ligases that can identify and mediate the ubiquitination of specific substrate proteins. All HERC ubiquitin ligases except HERC6 have been assigned one or more than one ubiquitination substrates. In all of HERCs, HERC1 and HERC2 have been widely studied, in contrast, there are no reported studies yet on protein ubiquitination mediated by HERC6. Dependent on the protein substrates, HERC proteins may act as a tumor suppressor or oncoprotein in specific cancer types. For example, HERC4 is believed to contribute to carcinogenesis of solid tumors such as lung cancer, but it suppresses the proliferation of myeloma cells. Conclusion: HERC proteins as ubiquitin ligases are widely involved in various cancers. Targeting at specific HERC proteins could be a strategy for the treatment of certain cancers.