The SP140-RESIST Pathway Regulates Interferon MRNA Stability and Antiviral Immunity

Overview

Journal bioRxiv

Date 2025 Feb 20

PMID 39974928

Authors

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

Affiliations

Soon will be listed here.

Abstract

Type I interferons (IFN-Is) are essential for antiviral immunity but must be tightly regulated. The conserved transcriptional repressor SP140 inhibits interferon beta () expression via an unknown mechanism. Here we report that SP140 does not directly repress transcription. Instead, SP140 negatively regulates mRNA stability by directly repressing the expression of a previously uncharacterized regulator we call RESIST (REgulated Stimulator of Interferon via Stabilization of Transcript, previously annotated as Annexin-2 Receptor). RESIST promotes mRNA stability by counteracting mRNA destabilization mediated by the Tristetraprolin (TTP) family of RNA-binding proteins and the CCR4-NOT deadenylase complex. SP140 localizes within nuclear bodies, punctate structures that play important roles in silencing DNA virus gene expression in the nucleus. Consistent with this observation, we found that SP140 inhibits replication of the gammaherpesvirus MHV68. The antiviral activity of SP140 was independent of its ability to regulate . Our results establish dual antiviral and interferon regulatory functions for SP140. We propose that SP140 and RESIST participate in antiviral effector-triggered immunity.

References

Wang H, Yang H, Shivalila C, Dawlaty M, Cheng A, Zhang F . One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell. 2013; 153(4):910-8. PMC: 3969854. DOI: 10.1016/j.cell.2013.04.025. View

Cook M, Bradstreet T, Webber A, Kim J, Santeford A, Harris K . The ZFP36 family of RNA binding proteins regulates homeostatic and autoreactive T cell responses. Sci Immunol. 2022; 7(76):eabo0981. PMC: 9832469. DOI: 10.1126/sciimmunol.abo0981. View

Barton E, Mandal P, Speck S . Pathogenesis and host control of gammaherpesviruses: lessons from the mouse. Annu Rev Immunol. 2011; 29:351-97. DOI: 10.1146/annurev-immunol-072710-081639. View

Mehta S, Cronkite D, Basavappa M, Saunders T, Adiliaghdam F, Amatullah H . Maintenance of macrophage transcriptional programs and intestinal homeostasis by epigenetic reader SP140. Sci Immunol. 2017; 2(9). PMC: 5549562. DOI: 10.1126/sciimmunol.aag3160. View

McLean C, Bristor D, Hiller M, Clarke S, Schaar B, Lowe C . GREAT improves functional interpretation of cis-regulatory regions. Nat Biotechnol. 2010; 28(5):495-501. PMC: 4840234. DOI: 10.1038/nbt.1630. View

Bulbrook D, Brazier H, Mahajan P, Kliszczak M, Fedorov O, Marchese F . Tryptophan-Mediated Interactions between Tristetraprolin and the CNOT9 Subunit Are Required for CCR4-NOT Deadenylase Complex Recruitment. J Mol Biol. 2018; 430(5):722-736. DOI: 10.1016/j.jmb.2017.12.018. View

Jones J, Staskawicz B, Dangl J . The plant immune system: From discovery to deployment. Cell. 2024; 187(9):2095-2116. DOI: 10.1016/j.cell.2024.03.045. View

Popovic B, Nicolet B, Guislain A, Engels S, Jurgens A, Paravinja N . Time-dependent regulation of cytokine production by RNA binding proteins defines T cell effector function. Cell Rep. 2023; 42(5):112419. PMC: 10242446. DOI: 10.1016/j.celrep.2023.112419. View

Bhattacharya B, Xiao S, Chatterjee S, Urbanowski M, Ordonez A, Ihms E . The integrated stress response mediates necrosis in murine Mycobacterium tuberculosis granulomas. J Clin Invest. 2020; 131(3). PMC: 7843230. DOI: 10.1172/JCI130319. View

10.

Jostins L, Ripke S, Weersma R, Duerr R, McGovern D, Hui K . Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012; 491(7422):119-24. PMC: 3491803. DOI: 10.1038/nature11582. View

11.

McGuire V, Rosner D, Ananieva O, Ross E, Elcombe S, Naqvi S . Beta Interferon Production Is Regulated by p38 Mitogen-Activated Protein Kinase in Macrophages via both MSK1/2- and Tristetraprolin-Dependent Pathways. Mol Cell Biol. 2016; 37(1). PMC: 5192081. DOI: 10.1128/MCB.00454-16. View

12.

Berger I, Fitzgerald D, Richmond T . Baculovirus expression system for heterologous multiprotein complexes. Nat Biotechnol. 2004; 22(12):1583-7. DOI: 10.1038/nbt1036. View

13.

Borden E . Interferons α and β in cancer: therapeutic opportunities from new insights. Nat Rev Drug Discov. 2019; 18(3):219-234. DOI: 10.1038/s41573-018-0011-2. View

14.

Sumida T, Dulberg S, Schupp J, Lincoln M, Stillwell H, Axisa P . Type I interferon transcriptional network regulates expression of coinhibitory receptors in human T cells. Nat Immunol. 2022; 23(4):632-642. PMC: 8989655. DOI: 10.1038/s41590-022-01152-y. View

15.

Hubel P, Urban C, Bergant V, Schneider W, Knauer B, Stukalov A . A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape. Nat Immunol. 2019; 20(4):493-502. DOI: 10.1038/s41590-019-0323-3. View

16.

Snyder B, Huang R, Burkholder A, Donahue D, Mahler B, Bortner C . Synergistic roles of tristetraprolin family members in myeloid cells in the control of inflammation. Life Sci Alliance. 2023; 7(1). PMC: 10616675. DOI: 10.26508/lsa.202302222. View

17.

Skene P, Henikoff S . An efficient targeted nuclease strategy for high-resolution mapping of DNA binding sites. Elife. 2017; 6. PMC: 5310842. DOI: 10.7554/eLife.21856. View

18.

Bjornevik K, Cortese M, Healy B, Kuhle J, Mina M, Leng Y . Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022; 375(6578):296-301. DOI: 10.1126/science.abj8222. View

19.

Tan X, Sun L, Chen J, Chen Z . Detection of Microbial Infections Through Innate Immune Sensing of Nucleic Acids. Annu Rev Microbiol. 2018; 72:447-478. DOI: 10.1146/annurev-micro-102215-095605. View

20.

Remick B, Gaidt M, Vance R . Effector-Triggered Immunity. Annu Rev Immunol. 2023; 41:453-481. DOI: 10.1146/annurev-immunol-101721-031732. View