期刊
IMMUNITY
卷 48, 期 3, 页码 487-+出版社
CELL PRESS
DOI: 10.1016/j.immuni.2018.01.014
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资金
- NIH [R01 AI10497, U19 AI109680, U19 AI083019, GM103422, AI107056, AI120943, AI109945]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [U19AI109680, R01AI104972, P01AI120943, R01AI107056, U19AI109945, U19AI083019, F32AI010497] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P41GM103422] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [S10OD016298] Funding Source: NIH RePORTER
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 (m(7) GpppN) 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 (m(7) GpppNm) or 50-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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