ISG15

ISG15, or interferon-stimulated gene 15, is a small ubiquitin-like modifier protein encoded by the ISG15 gene in humans. Expression is rapidly upregulated by type I interferons and during viral infection.

ISG15 is synthesized as a precursor that is processed to a mature form consisting of two tandem ubiquitin-like domains, ending in a conserved C-terminal LRLRGG motif required for conjugation to target proteins. The protein can function intracellularly as a modifier or be secreted as a cytokine-like molecule.

ISGylation, the covalent attachment of ISG15 to lysine residues on substrates, is mediated by a conjugation cascade similar to ubiquitination. The E1 activating enzyme UBA7 activates ISG15 in an ATP-dependent step, the E2 enzyme UBE2L6 transfers ISG15, and E3 ligases such as HERC5 facilitate transfer to substrates. Deconjugation is carried out predominantly by the isopeptidase USP18 (UBP43), which reverses ISGylation.

Biological roles: ISGylation modulates the function, stability, and localization of a variety of proteins, including components of antiviral signaling pathways, and has been associated with reduced replication of several viruses in experimental systems. In addition to ISGylation, secreted ISG15 can act as a cytokine-like molecule that stimulates immune cell responses, including natural killer cells and interferon-gamma production.

Clinical and research notes: The ISG15 pathway is an integral part of the type I interferon response. Dysregulation of ISG15 signaling, USP18 activity, or related components can influence antiviral defense and inflammatory signaling in experimental models, and is studied for its relevance to infectious diseases and immune disorders.