Understanding the translation landscape at the host pathogen interface (360G-Wellcome-202471_Z_16_Z)

Viral infection triggers the expression of hundreds of interferon-stimulated genes (ISGs) that serve to restrict viral replication and spread. The function of one of the most highly upregulated ISGs, the IFN-induced protein with tetratricopeptide repeats (IFIT)1 is still not clear. Most cellular mRNAs have a 5´-N7-methylguanosine (m7G) cap and are also methlylated on the first base (cap1-RNA). I recently showed that IFIT1 bound tightly to mRNAs that had an m7G cap but lacked 2´-O-methylation of the first base (cap0-RNA) and inhibited their translation. To date, the only viruses restricted by this cap0 binding activity are mutants encoding inactive 2´-O-methyltransferases. My hypothesis is that IFIT1 influences the anti-viral response via interactions with host proteins and RNAs, modifying the translational landscape of the infected cell, while imposing a strong evolutionary pressure on viruses to maintain a cap1-RNA structure. I will determine how and which cellular RNAs IFIT1 and the related IFIT1B (that can also bind cap1-RNA) bind in the cell, the fate of these bound RNAs and the impact RNA binding has on IFIT1 protein-protein interactions and the cellular translation profile. By understanding the impact of IFIT1 on the cell we will gain insight into its role in the host antiviral response.