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 data reveal that IFIT3 or the IFIT2:IFIT3 heterodimer can stimulate cap0 mRNA binding, and thus translation inhibition, by IFIT1. We next sought to identify how IFIT1 and IFIT3 interact. Murine Ifit3, which does not precipitate with murine Ifit1b1 (14) , has a large deletion at the C terminus ( Figure S5 ) when compared to human IFIT3. As a result of this deletion, mouse Ifit3 lacks a 'YxxxL' structural motif present in both human IFIT3 and IFIT1 ( Figure 5A and B) recently reported to promote IFIT1 concentration dependent dimerisation (BioRxiv: https://doi.org/10.1101/152850). Our SEC-MALS analysis demonstrates that the IFIT1:IFIT3 interaction is more stable than the IFIT1:IFIT1 interaction (compare Figure 2A and Figure S2A ). We therefore hypothesised that the proposed IFIT1 dimerisation motif is the site of interaction between IFIT1 and IFIT3. author/funder. All rights reserved. No reuse allowed without permission.