Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation
Abstract
During virus infection, the adaptor proteins MAVS and STING transduce signals from the cytosolic nucleic acid sensors RIG-I and cGAS, respectively, to induce type I interferons (IFNs) and other antiviral molecules. Here we show that MAVS and STING harbor two conserved serine and threonine clusters that are phosphorylated by the kinases IKK and/or TBK1 in response to stimulation. Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1. We further show that TRIF, an adaptor protein in Toll-like receptor signaling, activates IRF3 through a similar phosphorylation-dependent mechanism. These results reveal that phosphorylation of innate adaptor proteins is an essential and conserved mechanism that selectively recruits IRF3 to activate the type I IFN pathway.
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On reaching the Golgi, STING recruits TBK1, which activates IRF3 and NF-κB, leading to expression of ISGs, type I interferons and other inflammatory cytokines.
“On reaching the Golgi compartment, STING then recruits TBK1, which then activates IRF3 and NF-κB, leading to the expression of interferon-stimulated genes (ISGs), type I interferons and other inflammatory cytokines (e.g., IL-6, IL-12).393–396”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [395]
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- Authors
- Liu, S., Cai, X., Wu, J., Cong, Q., Chen, X., Li, T., Du, F., Ren, J., Wu, Y.-T., Grishin, N. V., & Chen, Z. J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Howard Hughes Medical Institute (US)
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
- Corresponding author
- Chen, Zhijian J.
- ORCID
- Venue
- Science
- Published
- 2015-03-13
- Volume
- 347
- Issue
- 6227
- Pages
- aaa2630-aaa2630
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2047365750
- Cited by
- 1,927
- References
- 4
- Citations by year
- 2026: 205 · 2025: 220 · 2024: 274 · 2023: 209 · 2022: 241 · 2021: 188 · 2020: 152 · 2019: 139 · 2018: 97 · 2017: 104 · 2016: 67 · 2015: 30
- FWCI
- 48.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- NIH (AI-93967, GM-63692, GM-094575)
- Welch Foundation (I-1389, I-1505)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- MAVS, STING, TRIF, IRF3 activation, protein phosphorylation, TBK1, IκB kinase, innate immune signaling, type I interferon, RIG-I, cGAS, adaptor proteins, Toll-like receptor signaling
- MeSH terms
- STING Protein, Amino Acid Sequence, Animals, Cell Line, Humans, Membrane Proteins, Molecular Sequence Data, Phosphorylation, Protein Binding, Recombinant Proteins, Serine, Signal Transduction, Interferon-alpha, Interferon-beta, Protein Serine-Threonine Kinases, Vesiculovirus, Sendai virus, Adaptor Proteins, Vesicular Transport, Adaptor Proteins, Signal Transducing, Interferon Regulatory Factor-3, Mice, I-kappa B Kinase, Ubiquitination, Protein Multimerization
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