Recruitment of phosphatase PP2A by RACK1 adaptor protein deactivates transcription factor IRF3 and limits type I interferon signaling
Open accessAbstract
The transcription factor IRF3 is a central regulator of type I interferon (IFN) signaling. The mechanisms underlying deactivation of IRF3 are poorly understood although many studies suggest that IRF3 activity is terminated through degradation after viral infection. Here we report that IRF3 is deactivated via dephosphorylation mediated by the serine and threonine phosphatase PP2A and its adaptor protein RACK1. The PP2A-RACK1 complex negatively regulated the IRF3 pathway after LPS or poly(I:C) stimulation or Sendai virus (SeV) infection. After challenge with LPS, poly(I:C), or low-titer SeV, activated IRF3 was dephosphorylated and returned to resting state without being degraded, although high-titer SeV infection triggered the degradation of IRF3. Furthermore, PP2A-deficient macrophages showed enhanced type I IFN signaling upon LPS, poly(I:C), and SeV challenge and protected mice from lethal vesicular stomatitis virus infection. Therefore, dephosphorylation of IRF3 is a deactivation mechanism that contributes to termination of IRF3-type I IFN signaling.
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Conditional knockout of Cα specifically in macrophages resulted in an elevated host antiviral response, as shown by increased protection of these mice from lethal infection with vesicular stomatitis virus.
“conditional KO of Cα specifically in macrophages, resulted in an elevated host antiviral response, as shown by an increased protection of these mice from lethal infection with the vesicular stomatitis virus (VSV) [84].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [84]
These data are consistent with a direct role for PP2A in IRF3 dephosphorylation, a process that appears to be mediated by the RACK1 adaptor protein.
“These data are thus consistent with a direct role for PP2A in IRF3 dephosphorylation, a process that appears to be mediated by the RACK1 adaptor protein [84].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [84]
This was associated with enhanced NF-κB signaling in peripheral blood mononuclear cells and increased type-I interferon signaling in peritoneal macrophages upon LPS or Sendai virus infection, with increased IRF3 Ser396 phosphorylation and increased Ifnb1, Isg15, and Rantes expression.
“This was associated with enhanced NF-κB signaling in peripheral blood mononuclear cells (PBMCs) and increased type-I interferon signaling in peritoneal macrophages, when stimulated with LPS or upon Sendai virus infection, as shown by increased interferon regulatory factor 3 (IRF3) phosphorylation (Ser396), and increased expression of Ifnb1, Isg15 and Rantes.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [84]
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References 36 · Cited by 127
- Authors
- Long, L., Deng, Y., Yao, F., Guan, D., Feng, Y., Jiang, H., Li, X., Hu, P., Lu, X., Wang, H., Li, J., Gao, X., & Xie, D.
- Affiliations
- Chinese Academy of Sciences (CN)
- Model Animal Research Center (CN)
- Corresponding author
- Xie, Dong
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 40
- Issue
- 4
- Pages
- 515-529
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W1965897766
- Cited by
- 127
- References
- 36
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 11 · 2023: 10 · 2022: 8 · 2021: 16 · 2020: 10 · 2019: 10 · 2018: 6 · 2017: 8 · 2016: 9 · 2015: 10 · 2014: 6
- FWCI
- 5.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- IRF3, protein phosphatase 2A, RACK1, type I interferon signaling, Sendai virus, macrophages, vesicular stomatitis virus, innate immunity, adaptor proteins, LPS, poly(I:C)
- MeSH terms
- Receptors for Activated C Kinase, Roundabout Proteins, Animals, HeLa Cells, Humans, Interferon Type I, Membrane Proteins, Mice, Transgenic, Nerve Tissue Proteins, Neuropeptides, Phosphorylation, Protein Binding, Receptors, Cell Surface, Vesicular stomatitis Indiana virus, Signal Transduction, Transgenes, Sendai virus, Interferon Regulatory Factor-3, Toll-Like Receptor 3, Toll-Like Receptor 4, Mice, Vesicular Stomatitis, Protein Phosphatase 2
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