Mouse Ifit1b is a cap1-RNA binding protein which inhibits mouse coronavirus translation and is regulated by complexing with Ifit1c.

Knock-out mouse models have been extensively used to study the antiviral activity of interferon-induced protein with tetratricopeptide repeats (IFIT). Human IFIT1 binds to cap0 (m7GpppN) RNA, which lacks methylation on the first and second cap-proximal nucleotides (cap1, m7GpppNm, and cap2, m7GpppNmNm, respectively). These modifications are signatures of 'self' in higher eukaryotes, while unmodified cap0-RNA is recognised as foreign and, therefore, potentially harmful to the host cell. IFIT1 inhibits translation at the initiation stage by competing with the cap-binding initiation factor complex, eIF4F, restricting infection by certain viruses that possess 'non-self' cap0-mRNAs. However, in mice and other rodents the IFIT1 orthologue has been lost and the closely-related Ifit1b has been duplicated twice, yielding three paralogues: Ifit1, Ifit1b and Ifit1c. While murine Ifit1 is similar to human IFIT1 in its cap0-RNA binding selectivity, the roles of Ifit1b and Ifit1c are unknown. Here, we found that Ifit1b preferentially binds to cap1-RNA, while binding is much weaker to cap0- and cap2-RNA. In murine cells, we show that Ifit1b can modulate host translation and restrict wildtype mouse coronavirus infection. We found that Ifit1c acts as a stimulatory cofactor for both Ifit1 and Ifit1b, promoting their translation inhibition. In this way, Ifit1c acts in an analogous fashion to human IFIT3, which is a cofactor to human IFIT1. This work clarifies similarities and differences between the human and murine IFIT families, to facilitate better design and interpretation of mouse models of human infection, and sheds light on the evolutionary plasticity of the IFIT family. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.