Human IFIT3 Modulates IFIT1 RNA Binding Specificity and Protein Stability

Publication date: Available online 8 March 2018
Source:Immunity
Author(s): Britney Johnson, Laura A. VanBlargan, Wei Xu, James P. White, Chao Shan, Pei-Yong Shi, Rong Zhang, Jagat Adhikari, Michael L. Gross, Daisy W. Leung, Michael S. Diamond, Gaya K. Amarasinghe
Although interferon-induced proteins with tetratricopeptide repeats (IFIT proteins) inhibit infection of many viruses by recognizing their RNA, the regulatory mechanisms involved remain unclear. Here we report a crystal structure of cap 0 (m⁷GpppN) RNA bound to human IFIT1 in complex with the C-terminal domain of human IFIT3. Structural, biochemical, and genetic studies suggest that IFIT3 binding to IFIT1 has dual regulatory functions: (1) extending the half-life of IFIT1 and thereby increasing its steady-state amounts in cells; and (2) allosterically regulating the IFIT1 RNA-binding channel, thereby enhancing the specificity of recognition for cap 0 but not cap 1 (m⁷GpppNm) or 5′-ppp RNA. Mouse Ifit3 lacks this key C-terminal domain and does not bind mouse Ifit1. The IFIT3 interaction with IFIT1 is important for restricting infection of viruses lacking 2′-O methylation in their RNA cap structures. Our experiments establish differences in the regulation of IFIT1 orthologs and define targets for modulation of human IFIT protein activity.

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Teaser

Prior studies have suggested that human IFIT1, unlike its mouse ortholog, might not recognize viral RNA molecules lacking 2′-O methylation on their cap structures. Johnson et al. report a crystal structure between cap 0 (m⁷GpppN) RNA bound to human IFIT1 in complex with the C-terminal domain (CTD) of human IFIT3. The CTD of IFIT3 bound to IFIT1 and allosterically regulated the IFIT1 RNA-binding channel and promoted selective recognition of cap 0 RNA. Functional studies demonstrated that IFIT3 interaction with IFIT1 was important for stabilizing IFIT1 expression and was required for restricting infection of viruses lacking 2′-O methylation in their RNA cap structures


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