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11:44
A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3
Published on: January 24, 2016
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Natural mutations in IFITM3 modulate post-translational regulation and toggle antiviral specificity
Alex A Compton1, Nicolas Roy2, Françoise Porrot2
1Virus & Immunity Unit, Institut Pasteur, Paris, France alex.compton@pasteur.fr schwartz@pasteur.fr.
EMBO Reports
|September 8, 2016
Summary
Interferon-induced transmembrane (IFITM) proteins, particularly IFITM3, block HIV-1 spread. Gene evolution created new IFITM3 variants with altered antiviral activity and specificity, enhancing host defense.
Area of Science:
- Virology
- Immunology
- Evolutionary Biology
Background:
- Interferon-induced transmembrane (IFITM) proteins are key host factors conferring resistance to various viral infections.
- IFITM proteins, especially IFITM3, are incorporated into Human Immunodeficiency Virus type 1 (HIV-1) virions, inhibiting viral fusion and cell-to-cell transmission.
Purpose of the Study:
- To investigate the role of IFITM3 mutations in HIV-1 inhibition and viral incorporation.
- To explore the evolutionary history and functional diversification of IFITM3 genes in primates.
Main Methods:
- Analysis of amino-terminal IFITM3 mutants affecting ubiquitination and endocytosis.
- Assessment of viral incorporation and fusion inhibition assays for HIV-1.
- Comparative genomic analysis of IFITM genes across primate species.
Main Results:
- IFITM3 mutants lacking ubiquitination and endocytosis sites showed increased virion incorporation and enhanced HIV-1 fusion inhibition.
- IFITM3 is the most ancient IFITM antiviral gene, with recurrent duplications observed in primate evolution.
- Primate-specific IFITM3 gene variants display altered localization and function, suggesting selection for modified antiviral activity.
- Enhanced HIV-1 restriction by certain IFITM3 variants correlated with reduced activity against Influenza A virus, indicating a trade-off in specificity.
Conclusions:
- Diversification of IFITM3 genes through evolution can broaden antiviral defense capabilities.
- Mutations affecting IFITM3 ubiquitination and endocytosis enhance its intrinsic antiviral potency against HIV-1.
- Evolutionary adaptations in IFITM3 lead to functional trade-offs, potentially optimizing defense against specific pathogens.
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