HERC5 Gene - Function, Mutations, and Disease Associations

HERC5 (HECT and RLD Domain Containing E3 Ubiquitin Protein Ligase 5) encodes a member of the HERC family of E3 ubiquitin ligases. The protein is strongly induced by type I interferons and functions as the primary E3 ligase for ISG15 conjugation (ISGylation) to target proteins, a key post-translational modification in antiviral innate immunity. HERC5 localizes to the cytoplasm and mediates ISG15 attachment to newly synthesized viral and host proteins, thereby restricting viral replication. It also participates in protein quality control by targeting misfolded proteins for ISGylation.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• ISG15 antiviral mechanism (Reactome: R-HSA-1169410)

• Interferon alpha/beta signaling (Reactome: R-HSA-909733)

• Ubiquitin-mediated proteolysis (KEGG: hsa04120)

• Protein ISGylation (UniProt: Q9UII4)

HERC5 is a 1024-amino-acid cytoplasmic E3 ubiquitin ligase containing a HECT domain and RLD (RCC1-like domain). It is the major ISG15 E3 ligase, conjugating ISG15 to lysine residues of target proteins in an interferon-dependent manner. The protein plays a critical role in antiviral defense by ISGylating viral proteins (e.g., influenza NS1, HIV-1 Gag) and host factors, leading to inhibition of viral replication. HERC5 also participates in protein quality control by targeting misfolded proteins for ISGylation and subsequent degradation.