Protein phosphatase 2A enables expression of interleukin 17 (IL-17) through chromatin remodeling
Open accessAbstract
Protein phosphatase 2A (PP2A) is a heterotrimeric serine/threonine phosphatase involved in essential cellular functions. T cells from patients with systemic lupus erythematosus (SLE) express high levels of the catalytic subunit of PP2A (PP2Ac). A mouse overexpressing PP2Ac in T cells develops glomerulonephritis in an IL-17-dependent manner. Here, using microarray analyses, we demonstrate that increased expression of PP2Ac grants T cells the capacity to produce an array of proinflammatory effector molecules. Because IL-17 is important in the expression of glomerulonephritis, we studied the mechanism through which PP2Ac dysregulation facilitates its production. We report that PP2Ac is involved in the regulation of the Il17 locus by enhancing histone 3 acetylation through a mechanism that involves activation of interferon regulatory factor 4. Increased histone 3 acetylation of the Il17 locus is shared between T cells of PP2Ac transgenic mice and patients with SLE. We propose that, by promoting the inflammatory capacity of T cells, PP2Ac dysregulation contributes to the pathogenesis of SLE. Background: Increased PP2A levels have been linked to autoimmunity in SLE patients and transgenic mice. Results: In T cells, PP2A overexpression increases the transcription of proinflammatory genes and facilitates chromatin accessibility at the Il17 locus. Conclusion: Increased levels of PP2A promote the inflammatory capacity of T cells. Significance: PP2A dysregulation may contribute to SLE by directly affecting lymphocyte gene expression.
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Microarray analysis in naive and activated CD4+ T-cells from this model revealed 124 upregulated and only 6 downregulated genes, with upregulated genes primarily encoding cytokines and chemokines, including IL-17.
“Additional microarray analysis in naïve and activated CD4 + T-cells from this model, revealed 124 upregulated and only 6 downregulated genes, with the upregulated genes primarily encoding cytokines and chemokines, including IL-17 [86].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [86]
Increased Histone H3 acetylation at Il17a and Il17b loci, alongside increased recruitment of IRF4, implies a role for PP2A in epigenetic regulation in T-cells.
“Mechanistically, increased Histone H3 acetylation at Il17a and Il17b loci was detected, alongside increased recruitment of IRF4, implying a role for PP2A in epigenetic regulation in T-cells.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [86]
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Self-citation
- Authors
- Apostolidis, S. A., Rauen, T., Hedrich, C. M., Tsokos, G. C., & Crispín, J. C.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Tsokos, George C.
- Crispín, José C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-09
- Volume
- 288
- Issue
- 37
- Pages
- 26775-26784
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3772223
- OpenAlex
- W2038119991
- Cited by
- 91
- References
- 70
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 8 · 2023: 7 · 2022: 7 · 2021: 10 · 2020: 10 · 2019: 9 · 2018: 8 · 2017: 7 · 2016: 12 · 2015: 6 · 2014: 1
- FWCI
- 5.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Funders
- Lupus Research Alliance
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (R01AI068787)
- Topics
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- protein phosphatase 2A, IL-17, systemic lupus erythematosus, T cells, histone H3 acetylation, chromatin remodeling, IRF4, glomerulonephritis, autoimmunity, pro-inflammatory gene expression, chromatin accessibility
- MeSH terms
- Animals, Chromatin, Gene Expression Regulation, Histones, Inflammation, Lupus Erythematosus, Systemic, Mice, Inbred C57BL, Mice, Transgenic, T-Lymphocytes, Catalytic Domain, Interleukin-17, Oligonucleotide Array Sequence Analysis, Chromatin Assembly and Disassembly, Mice, rho-Associated Kinases, Protein Phosphatase 2
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