Journal article
Transcriptional repressor Capicua is a gatekeeper of cell-intrinsic interferon responses
Cell host & microbe, Vol.33(4), pp.512-528.e7
04/2025
DOI: 10.1016/j.chom.2025.02.017
PMCID: PMC11985295
PMID: 40132591
Abstract
Early detection of viral infection and rapid activation of host antiviral defenses through transcriptional upregulation of interferons (IFNs) and IFN-stimulated genes (ISGs) are critical for controlling infection. However, aberrant production of IFN in the absence of viral infection leads to auto-inflammation and can be detrimental to the host. Here, we show that the DNA-binding transcriptional repressor complex composed of Capicua (CIC) and Ataxin-1 like (ATXN1L) binds to an 8-nucleotide motif near IFN and ISG promoters and prevents erroneous expression of inflammatory genes under homeostasis in humans and mice. By contrast, during respiratory viral infection, activation of the mitogen-activated protein kinase (MAPK) pathway results in rapid degradation of the CIC-ATXN1L complex, thereby relieving repression and allowing for robust induction of IFN and ISGs. Together, our studies define a new paradigm for host regulation of IFN and ISGs through the evolutionarily conserved CIC-ATXN1L transcriptional repressor complex during homeostasis and viral infection.
Details
- Title: Subtitle
- Transcriptional repressor Capicua is a gatekeeper of cell-intrinsic interferon responses
- Creators
- Senthamizharasi Manivasagam - University of IowaJulianna Han - University of ChicagoAthmane Teghanemt - University of IowaHenry Keen - University of IowaBoopathi Sownthirarajan - University of IowaBoyang Cheng - University of IowaAbhiraj Singh - Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, USAAbigail Lewis - University of IowaOlivia A Vogel - University of IowaGayathri Loganathan - University of IowaLei Huang - University of ChicagoMaryline Panis - New York UniversityDavid K Meyerholz - University of IowaBenjamin tenOever - New York UniversityJasmine T Perez - University of ChicagoSanthakumar Manicassamy - Augusta University HealthPriya D Issuree - University of IowaBalaji Manicassamy - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Cell host & microbe, Vol.33(4), pp.512-528.e7
- DOI
- 10.1016/j.chom.2025.02.017
- PMID
- 40132591
- PMCID
- PMC11985295
- NLM abbreviation
- Cell Host Microbe
- ISSN
- 1931-3128
- eISSN
- 1934-6069
- Publisher
- CELL PRESS
- Grant note
- NIH Molecular and Cellular Biology training program at The University of Chicago: T32GM007183 NIH Diversity Supplement: R01AI123359-02S1, 3R01AI16593202S1 NIAID grant: R01AI123359 NIGMS: 1R35GM154831-01
We would like to thank Dr. Adolfo Garcia-Sastre (Mount Sinai School of Medicine) for sharing numerous reagents. EMCV, Zika virus MR766, and recombinant HA proteins were obtained from BEI Resources (NIAID) . Julianna Han and Olivia Vogel were partly supported by the NIH Molecular and Cellular Biology training program at The University of Chicago (T32GM007183) . Julianna Han was supported by the NIH Diversity Supplement (R01AI123359-02S1) . Abigail Lewis was supported by the Primary Caregiver Technical Assistance Supplement awarded to Dr. Senthamizharasi Manivasagam (PCTAS, 3R01AI16593202S1) . Drs. Balaji Manicassamy and Priya Issuree were partly supported by NIAID grant (R01AI123359) and NIGMS (1R35GM154831-01) . The funders
- Language
- English
- Electronic publication date
- 03/18/2025
- Date published
- 04/2025
- Academic Unit
- Microbiology and Immunology; Infectious Diseases; Pathology; Internal Medicine; Iowa Institute of Human Genetics
- Record Identifier
- 9984802193702771
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