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

Viruses have evolved numerous mechanisms to circumvent detection and inhibition by IFIT1. For example, members of the Flaviviridae and Coronaviridae families that replicate in the cytoplasm and rely on cap-dependent translation of their single-stranded positive-sense RNA genomes, encode their own 2´-O-methyltransferases. Disruption of methyltransferase activity increases susceptibility of the flaviviruses West Nile virus, japanese encephalitis virus and dengue virus (15) (16) (17) (18) (19) and the coronaviruses murine hepatitis virus and severe acute respiratory syndrome virus (20, 21) to IFIT1 restriction. Interestingly, enzymatically 2´-O-methylated, capped mRNAs from parainfluenza virus 5 display differential translational sensitivity to IFIT1 in vitro, while wild type middle east respiratory syndrome coronavirus (MERS) replication was enhanced upon IFIT1 depletion suggesting that factors other than 5´ end methylation can influence IFIT1 recognition (22, 23) . By contrast, alphaviruses, such as the emerging human pathogen chikungunya virus, also rely on cap-dependent translation but lack a virally encoded 2´-O-methyltranferase, thus possessing viral mRNAs with a cap0 structure at the 5´ end (24) . Recent evidence suggests that stable secondary structure at the 5´ end of alphaviral genomes protects the viral RNAs from IFIT1 restriction (25, 26) . IFIT1 may also affect translation through interaction with eIF3 (27) , while its direct binding to the viral E1 protein restricts human papilloma virus replication (28) .