ISG15 ubiquitin-like modifier (ISG15) (ISG15)

ISG15 ubiquitin-like modifier (ISG15) is a 15 kDa protein that is rapidly induced by type I interferons and serves as a critical component of the innate immune system [UniProt: P05161, NCBI Gene: 9636]. It functions through two primary mechanisms: intracellularly, it covalently conjugates to target proteins in a process called ISGylation, which modulates their stability and activity; and extracellularly, it acts as a cytokine to stimulate the production of interferon-gamma and activate natural killer cells [PubMed: 35273453, 29434382]. In the context of oncology, ISG15 is frequently overexpressed and is associated with poor prognosis, as it can promote tumor cell proliferation, migration, and resistance to chemotherapy [PubMed: 29731958]. Conversely, its role in viral infections is primarily protective, where it inhibits the replication of various viruses, including influenza and HIV-1 [PubMed: 29434382]. Therapeutic strategies targeting ISG15, such as small molecule inhibitors of the ISGylation pathway or USP18 inhibitors, are currently being explored to treat certain cancers and inflammatory conditions [PubMed: 35273453, Mission Therapeutics].

Other names

Interferon-stimulated gene 15G1P2IFI15IP15UCRPUbiquitin cross-reactive proteinInterferon-induced 17 kDa protein

Modulation of the ISGylation enzymatic cascade (E1/E2/E3 ligases) to reduce pro-tumorigenic signaling, or inhibition of the de-ISGylating enzyme USP18 to stabilize ISG15-conjugates and enhance antiviral or anti-tumor immune responses [PubMed: 29731958, 35273453].