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Regulation of human interferon signaling by transposon exonization
Giulia Irene Maria Pasquesi1, Holly Allen2, Atma Ivancevic2
1BioFrontiers Institute and Department of Molecular, Cellular & Developmental Biology, University of Colorado Boulder, Boulder, CO 80309, USA; Crnic Institute Boulder Branch, BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80303, USA.
Cell
|December 13, 2024
Summary
Transposable elements regulate human immune signaling through alternative splicing. A transposon-derived variant of the type I interferon receptor (IFNAR2) acts as a decoy, inhibiting immune responses, including against SARS-CoV-2.
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- Innate immune signaling is crucial for host defense but requires strict regulation to prevent inflammation and autoimmunity.
- Alternative splicing is a key mechanism for generating protein diversity and regulating gene expression.
Purpose of the Study:
- To investigate the role of transposable elements in regulating innate immune signaling in human cells.
- To identify functional protein variants of immune genes generated by transposon exonization.
Main Methods:
- Analysis of long-read transcriptome datasets to identify exonization events.
- Characterization of transposon-derived isoforms of immune genes, including IFNAR2.
- Functional assays to assess the inhibitory activity of the IFNAR2 variant.
Main Results:
- Numerous transposon exonization events were identified, generating functional protein variants of immune genes.
- A primate-specific, transposon-derived isoform of IFNAR2 is highly expressed across human tissues.
- This IFNAR2 variant functions as a potent decoy receptor, inhibiting interferon signaling, even during SARS-CoV-2 infection.
Conclusions:
- Alternative splicing of transposable element exons is a significant mechanism controlling innate immune signaling.
- Transposon-derived IFNAR2 acts as a novel regulator of interferon responses.
- This finding reveals a primate-specific immune regulatory axis involving transposable elements.
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