Ubiquitin-like protein ISG15 and Interferon-induced protein with tetratricopeptide repeats 1 antiviral response pathway (ISG15/IFIT1 pathway)

The Ubiquitin-like protein ISG15 and Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1/ISG56) are essential effectors of the innate immune system's antiviral response. ISG15 is a ubiquitin-like modifier that undergoes ISGylation, a process that targets both host and viral proteins to inhibit viral replication and stabilize key immune signaling molecules (UniProt P05161). IFIT1, or ISG56, functions as an RNA-binding protein that recognizes viral mRNA lacking 2'-O-methylation or containing 5'-triphosphates, thereby blocking viral translation (UniProt P09914). These genes are transcriptionally activated by Type I and III interferons through the JAK-STAT signaling cascade, creating a robust antiviral state within the cell (PubMed: 32404431). In clinical practice, this pathway is a primary target for treating chronic viral infections like Hepatitis B and C, and its dysregulation is implicated in autoimmune interferonopathies and certain cancers. Therapeutic strategies include the administration of exogenous interferons to stimulate the pathway or the use of small molecules like TLR agonists to induce endogenous ISG expression (PubMed: 28410405).

Other names

ISG15ISG56IFIT1Interferon-induced 17 kDa proteinUbiquitin cross-reactive proteinUCRPG1P2IFI15G10P1IFI-56KIFN-stimulated gene 15IFN-stimulated gene 56

Drugs targeting this pathway typically act as agonists for interferon receptors or toll-like receptors to induce the expression of ISG15 and IFIT1. ISG15 then inhibits viral replication through protein ISGylation, while IFIT1 sequesters viral mRNA to prevent translation. This coordinated response effectively halts the viral life cycle at multiple stages.