SP140–RESIST pathway regulates interferon mRNA stability and antiviral immunity

Kristen C. Witt, Adam Dziulko, Joohyun An, Filip Pekovic, Arthur Xiuyuan Cheng, Grace Y. Liu, Ophelia Vosshall Lee, David J. Turner, Azra Lari, Moritz M. Gaidt, Roberto Chavez, Stefan A. Fattinger, Preethy Abraham, Harmandeep Dhaliwal, Angus Y. Lee, Dmitri I. Kotov, Laurent Coscoy, Britt A. Glaunsinger, Eugene Valkov, Edward B. Chuong and Russell E. Vance ()
Additional contact information
Kristen C. Witt: University of California
Adam Dziulko: University of Colorado Boulder
Joohyun An: University of California
Filip Pekovic: National Institutes of Health
Arthur Xiuyuan Cheng: University of California
Grace Y. Liu: University of California
Ophelia Vosshall Lee: University of California
David J. Turner: National Institutes of Health
Azra Lari: University of California
Moritz M. Gaidt: University of California
Roberto Chavez: University of California
Stefan A. Fattinger: University of California
Preethy Abraham: University of California
Harmandeep Dhaliwal: University of California
Angus Y. Lee: University of California
Dmitri I. Kotov: University of California
Laurent Coscoy: University of California
Britt A. Glaunsinger: University of California
Eugene Valkov: National Institutes of Health
Edward B. Chuong: University of Colorado Boulder
Russell E. Vance: University of California

Nature, 2025, vol. 643, issue 8074, 1372-1380

Abstract: Abstract Type I interferons are essential for antiviral immunity1 but must be tightly regulated2. The conserved transcriptional repressor SP140 inhibits interferon-β (Ifnb1) expression through an unknown mechanism3,4. Here we report that SP140 does not directly repress Ifnb1 transcription. Instead, SP140 negatively regulates Ifnb1 mRNA stability by directly repressing the expression of a previously uncharacterized regulator that we call RESIST (regulated stimulator of interferon via stabilization of transcript; previously annotated as annexin 2 receptor). RESIST promotes Ifnb1 mRNA stability by counteracting Ifnb1 mRNA destabilization mediated by the tristetraprolin (TTP) family of RNA-binding proteins and the CCR4–NOT deadenylase complex. SP140 localizes within punctate structures called nuclear bodies that have important roles in silencing DNA-virus gene expression in the nucleus3. Consistent with this observation, we find that SP140 inhibits replication of the gammaherpesvirus MHV68. The antiviral activity of SP140 is independent of its ability to regulate Ifnb1. Our results establish dual antiviral and interferon regulatory functions for SP140. We propose that SP140 and RESIST participate in antiviral effector-triggered immunity5,6.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-025-09152-2 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:643:y:2025:i:8074:d:10.1038_s41586-025-09152-2

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-025-09152-2

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().