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The SP140-RESIST pathway regulates interferon mRNA stability and antiviral immunity
Kristen C Witt1,2,3, Adam Dziulko4, Joohyun An2,3
1Howard Hughes Medical Institute, University of California, Berkeley, CA, USA.
Biorxiv : the Preprint Server for Biology
|February 20, 2025
Summary
The transcriptional repressor SP140 regulates antiviral immunity by controlling interferon beta mRNA stability, not transcription. It achieves this by repressing RESIST, a protein that stabilizes the mRNA.
Area of Science:
- Immunology
- Molecular Biology
- Virology
Background:
- Type I interferons (IFN-Is) are crucial for antiviral defense but require strict regulation.
- SP140 is a known transcriptional repressor that inhibits interferon beta (Ifnb1) expression through an unclear mechanism.
Purpose of the Study:
- To elucidate the mechanism by which SP140 regulates Ifnb1 expression.
- To identify novel regulators involved in interferon mRNA stability and antiviral responses.
Main Methods:
- Investigated SP140's direct effect on Ifnb1 transcription.
- Assessed SP140's impact on Ifnb1 mRNA stability.
- Identified and characterized RESIST (Annexin-2 Receptor) as a novel regulator.
- Examined the interaction between SP140, RESIST, TTP, and the CCR4-NOT complex.
- Evaluated SP140's antiviral activity against gammaherpesvirus MHV68.
Main Results:
- SP140 does not directly repress Ifnb1 transcription.
- SP140 inhibits Ifnb1 mRNA stability by repressing RESIST expression.
- RESIST stabilizes Ifnb1 mRNA by counteracting TTP and CCR4-NOT mediated destabilization.
- SP140 exhibits antiviral activity against MHV68, independent of Ifnb1 regulation.
Conclusions:
- SP140 possesses dual functions: regulating interferon mRNA stability and direct antiviral activity.
- SP140 represses RESIST, a key stabilizer of Ifnb1 mRNA.
- SP140 and RESIST are involved in effector-triggered antiviral immunity.
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