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
- Russell E. Vance
2025-06-11
Type I interferons are essential for antiviral immunity 1 but must be tightly regulated 2 . The conserved transcriptional repressor SP140 inhibits interferon-β ( Ifnb1 ) expression through an unknown mechanism 3,4 . 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 nucleus 3 . 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 immunity 5,6 .