Human IFIT3 Modulates IFIT1 RNA Binding Specificity and Protein Stability.

Area of Science:

• Virology
• Structural Biology
• Immunology

Background:

• Interferon-induced proteins with tetratricopeptide repeats (IFIT proteins) are crucial for innate immunity against viral infections.
• IFIT proteins function by recognizing viral RNA, but their regulatory mechanisms and specificity are not fully understood.
• The precise roles of specific IFIT proteins, like IFIT1 and IFIT3, in cellular antiviral responses require further elucidation.

Purpose of the Study:

• To elucidate the regulatory mechanisms of human IFIT1-mediated viral RNA recognition.
• To investigate the structural and functional interplay between human IFIT1 and IFIT3.
• To understand the species-specific differences in IFIT protein regulation and their impact on antiviral activity.

Main Methods:

• Crystal structure determination of human IFIT1 in complex with cap 0 RNA and the C-terminal domain of human IFIT3.
• Biochemical assays to assess RNA binding affinity and specificity.
• Genetic studies to evaluate the functional significance of the IFIT3-IFIT1 interaction in cellular antiviral responses.

Main Results:

• The crystal structure reveals how human IFIT3 binds to IFIT1, influencing its RNA-binding channel.
• IFIT3 binding enhances IFIT1's half-life and allosterically modulates its specificity for cap 0 RNA over cap 1 or 5'-ppp RNA.
• Mouse Ifit3 lacks the critical C-terminal domain for IFIT1 interaction, highlighting species-specific regulation.

Conclusions:

• Human IFIT3 acts as a dual regulator of IFIT1, stabilizing it and enhancing its specificity for viral RNA.
• The IFIT3-IFIT1 interaction is essential for restricting viruses with unmethylated RNA caps.
• These findings reveal distinct regulatory mechanisms for IFIT1 orthologs and identify targets for modulating antiviral immunity.