A Death-Promoting Role for ISG54/IFIT2

The cellular responses to infection are many, and include programmed cell death to inhibit microbial dissemination and the production and secretion of interferons (IFNs), which confer resistance to uninfected cells. In addition to the antimicrobial effects of IFNs, these cytokines have been used clinically for the treatment of various neoplasias to inhibit proliferation and stimulate apoptosis. However, the precise mechanisms of action of IFNs remain to be completely understood. One of the primary response genes induced after an infection or treatment with type I or III IFN is known as IFN-stimulated gene 54 (ISG54) or IFN-induced gene with tetratricopeptide repeats 2 (IFIT2). ISG54/IFIT2 is a member of a family of IFN-induced genes related in the sequence and structure. Expression of this protein has been found to promote cellular apoptosis by a mitochondrial pathway dependent on the action of Bcl2 proteins. ISG54/IFIT2 does not function as a monomer, and it forms complexes with itself and with the related ISG56/IFIT1 and ISG60/IFIT3 proteins to elicit complex cellular responses. The apoptotic response to ISG54/IFIT2 may contribute to other functions that have been reported, including translational regulation, inhibition of tumor colonization, and protection against a lethal viral infection.