IFIT3 and IFIT2/3 promote IFIT1-mediated translation inhibition by enhancing binding to non-self RNA

Renata C Fleith; Harriet V Mears; Edward Emmott; Stephen C Graham; Daniel S Mansur; Trevor R Sweeney

Our IFIT2:IFIT3 interaction studies have important implications for our understanding of IFIT complex assembly and biology. Overexpression of IFIT2 was previously reported to induce apoptosis (29, 39) , while co-expression with IFIT3 but not IFIT1 blocked this effect (29) . Moreover, depletion of IFIT3 induced cell death in the U549 human carcinoma cell line, an effect potentiated by co-infection with Dengue virus (40) . Our data would suggest that the homodimeric form of IFIT2 may be responsible for this phenotype, and that co-expression of IFIT3 may mitigate this effect by disrupting IFIT2 dimerisation. It is currently not clear why the cell would evolve such a mechanism for inducing programmed cell death. One potential hypothesis is that dysregulation of ISG induction, perhaps due to infection, could perturb the balance of IFIT2 and IFIT3, promoting cell death to restrict pathogen spread.