HERC5

Major E3 ligase for ISG15 conjugation. Functions as part of the ISGylation machinery that recognizes target proteins in a broad and relatively non-specific manner. Physically associated with polyribosomes, broadly modifies newly synthesized proteins in a cotranslational manner. Acts as a positive regulator of innate antiviral response in cells induced by interferon by mediating ISGylation of proteins involved in innate immunity, such as CGAS, IRF3, IFIH1/MDA5 and STING1. Catalyzes ISGylation of IRF3 which results in sustained activation, it attenuates IRF3-PIN1 interaction, which antagonizes IRF3 ubiquitination and degradation, and boosts the antiviral response. Also regulates innate antiviral response by mediating ISGylation of CGAS and STING1, thereby promoting activation of cGAS-STING signaling. Catalyzes ISGylation of IFIH1/MDA5, promoting IFIH1/MDA5 oligomerization and immune signal transduction. Also regulates innate immunity by catalyzing ISGylation of viral proteins: newly translated viral proteins are primary targets of ISG15 in interferon-stimulated cells. Interferes with the function of key viral structural proteins such as ebolavirus structural protein VP40 or HIV-1 protein GAG. Catalyzes ISGylation of influenza A viral NS1 which attenuates virulence; ISGylated NS1 fails to form homodimers and thus to interact with its RNA targets. Catalyzes ISGylation of papillomavirus type 16 L1 protein which results in dominant-negative effect on virus infectivity. Mediates ISGylation of the phosphatase PTEN leading to its degradation, thus alleviating its suppression of the PI3K-AKT signaling pathway and promoting the production of cytokines that facilitate bacterial clearance. Promotes parkin/PRKN ubiquitin E3 ligase activity by suppressing the intramolecular interaction that maintains its autoinhibited conformation..

Function from UniProtKB (Q9UII4), read 2026-09-23. CC BY 4.0.