Protein phosphatase subunit G5PR that regulates the JNK-mediated apoptosis signal is essential for the survival of CD4 and CD8 double-positive thymocytes
Abstract
Early T lineage cells are selected in the thymus by the specific recognition of peptide components presented by MHC molecules on the surface of thymic epithelial cells and dendritic cells. As a potential regulator of the apoptotic and survival signals, the protein phosphatase 2A-component G5PR regulates Bim phosphorylation in B-cells. Here, we studied whether G5PR is involved in the regulation of the similar apoptotic pathway for cell survival during the selection of thymocytes. T-cell-specific G5PR knockout (G5pr(-/-)) mice displayed thymic atrophy, significant reduction in thymocyte numbers, particularly a 10-fold decrease in the number of CD4 and CD8 double-positive (DP) thymocytes and few mature single-positive (SP) cells. G5pr(-/-) thymocytes exhibited normal potential of proliferation and differentiation during the transition from double-negative (DN) to DP stage, but significantly increased susceptibility to apoptosis at the DP stage. G5PR deficiency did not affect on Bim activation in thymocytes, but caused hyper-activation of JNK and Caspase-3 with augmented Fas ligand (FasL) expression, indicating that G5PR regulates the thymocyte unique apoptotic signal involved in JNK-mediated Caspase-3 activation but not in Bim activation. G5PR is essential for the survival of DP cells during thymocyte development.
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T-cell-specific loss of G5PR led to thymic atrophy and 10-fold reduced thymocyte numbers due to enhanced sensitivity of double positive thymocytes to apoptosis, while their proliferation and differentiation potential remained unaffected.
“T-cell-specific loss of G5PR lead to thymic atrophy and 10-fold reduced thymocyte numbers, due to enhanced sensitivity of double positive (DP) thymocytes to apoptosis, while their proliferation and differentiation potential remained unaffected [79].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [79]
Prolonged JNK activation and increased FasL expression explained the considerable reduction in double positive thymocytes and the nearly complete loss of single positive T-cells in the thymus.
“Together with a prolonged JNK activation and increased FasL expression, this explained the considerable reduction in DP thymocytes and the nearly complete loss of single positive T-cells in the thymus [79].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [79]
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- Authors
- Xing, Y., Wang, X., Igarashi, H., Kawamoto, H., & Sakaguchi, N.
- Affiliations
- Kumamoto University (JP)
- RIKEN (JP)
- Corresponding author
- Sakaguchi, Nobuo
- Venue
- Molecular Immunology
- Publisher
- Elsevier BV
- Published
- 2008-04
- Volume
- 45
- Issue
- 7
- Pages
- 2028-2037
- ISSN
- 0161-5890 (ISSN-L)
- OpenAlex
- W2031529853
- Cited by
- 15
- References
- 50
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2022: 2 · 2021: 2 · 2018: 1 · 2016: 1 · 2014: 1 · 2013: 1
- FWCI
- 0.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science
- Core Research for Evolutional Science and Technology
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- protein phosphatase 2A, JNK signaling, apoptosis, T cell development, double-positive thymocytes, CD4 and CD8 T cells, thymic atrophy, Fas ligand, caspase-3, building information modeling, thymocyte survival, knockout mice
- MeSH terms
- Animals, Cell Count, Cell Differentiation, Cell Survival, Enzyme Activation, Flow Cytometry, Phosphoprotein Phosphatases, Thymus Gland, CD4-Positive T-Lymphocytes, Apoptosis, CD8-Positive T-Lymphocytes, MAP Kinase Signaling System, Protein Subunits, JNK Mitogen-Activated Protein Kinases, Cell Proliferation, Mice, Membrane Potential, Mitochondrial, Caspase 3, Fas Ligand Protein
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