A Novel Non–Mammalian-Specific HERC7 Negatively Regulates IFN Response through Degrading RLR Signaling Factors

Abstract

Abstract The small HERC family currently comprises four members (HERC3–6) involved in the regulation of various physiological activities. Little is known about the role of HERCs in IFN response. In this study, we identify a novel fish HERC member, named crucian carp HERC7, as a negative regulator of fish IFN response. Genome-wide search of homologs and comprehensive phylogenetic analyses reveal that the small HERC family, apart from HERC3–6 that have been well-characterized in mammals, contains a novel HERC7 subfamily exclusively in nonmammalian vertebrates. Lineage-specific and even species-specific expansion of HERC7 subfamily in fish indicates that crucian carp HERC7 might be species-specific. In virally infected fish cells, HERC7 is induced by IFN and selectively targets three retinoic acid–inducible gene-I–like receptor signaling factors for degradation to attenuate IFN response by two distinct strategies. Mechanistically, HERC7 delivers mediator of IFN regulatory factor 3 activator and mitochondrial antiviral signaling protein for proteasome-dependent degradation at the protein level and facilitates IFN regulatory factor 7 transcript decay at the mRNA level, thus abrogating cellular IFN induction to promote virus replication. Whereas HERC7 is a putative E3 ligase, the E3 ligase activity is not required for its negative regulatory function. These results demonstrate that the ongoing expansion of the small HERC family generates a novel HERC7 to fine-tune fish IFN antiviral response.