The ISG15 gene (ISG15 stands for "Ubiquitin Like Modifier") is a protein-coding gene localized to chromsome 1p36.33. The protein encoded by the ISG15 gene is a ubiquitin-like protein that is attached to intracellular target proteins upon activation by interferon-alpha and interferon-beta. The protein encoded by this gene has chemotactic activity against neutrophils. Furthermore, it causes the alignment of ligated target proteins to intermediate filaments, cell-to-cell signaling and antiviral activity in viral infections.
The ubiquitin-like protein, which plays a key role in the innate immune response to viral infections, develops its effect either through its conjugation to a target protein (ISGylation - Note: "ISGylation" refers to the binding of a specific protein (e.g. STING) with a second, small protein, ISG15) or through its action as a free or unconjugated protein. ISGylation involves a cascade of enzymatic reactions involving E1, E2 and E3 enzymes that catalyze the conjugation of ISG15 to a lysine residue in the target protein.
The target proteins of the ubiquitin-like protein include IFIT1, MX1/MxA, PPM1B, UBE2L6, UBA7, CHMP5, CHMP2A, CHMP4B and CHMP6. Isgylation of the viral sensor IFIH1/MDA5 promotes IFIH1/MDA5 oligomerization and triggers activation of innate immunity against a range of viruses, including coronaviruses, flaviviruses and picornaviruses. The encoded protein exhibits antiviral activity against both DNA and RNA viruses (see viruses, classification below), including influenza A, HIV-1 and Ebola virus. Inhibits HIV-1 and Ebola viruses by interrupting viral budding.
The secreted form of ISG15 can induce the proliferation of natural killer cells, act as a chemotactic factor for neutrophils and, as an IFN-gamma-inducing cytokine, play an essential role in antimycobacterial immunity .