Mitochondrial localization and pro-apoptotic effects of the interferon-inducible protein ISG12a

ISG12a is one of the most highly induced genes following treatment of cells with type I interferons (IFNs). The encoded protein belongs to a family of poorly characterized, low molecular weight IFN-inducible proteins that includes 6-16 (G1P3), 1-8U (IFITM3), and 1-8D (IFITM2). Our studies demonstrate that the ISG12a protein associates with or inserts into the mitochondrial membrane. Transient expression of ISG12a led to decreased viable cell numbers and enhanced sensitivity to DNA-damage induced apoptosis, effects that were blocked by Bcl-2 co-expression or treatment with a pan-caspase inhibitor. ISG12a enhanced etoposide induced cytochrome c release, Bax activation and loss of mitochondrial membrane potential. siRNA-mediated inhibition of ectopic ISG12a protein expression prevented the sensitization to etoposide-induced apoptosis and also decreased the ability of IFN-beta pretreatment to sensitize cells to etoposide, thereby demonstrating a role for ISG12a in this process. These data suggest that ISG12a contributes to IFN-dependent perturbation of normal mitochondrial function, thus adding ISG12a to a growing list of IFN-induced proteins that impact cellular apoptosis.