Protein phosphatase 2A has an essential role in promoting thymocyte survival during selection

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Abstract
The development of thymocytes to mature T cells in the thymus is tightly controlled by cellular selection, in which only a small fraction of thymocytes equipped with proper quality of TCRs progress to maturation. It is pivotal to protect the survival of the few T cells, which pass the selection. However, the signaling events, which safeguard the cell survival in thymus, are not totally understood. In this study, protein Ser/Thr phosphorylation in thymocytes undergoing positive selection is profiled by mass spectrometry. The results revealed large numbers of dephosphorylation changes upon T cell receptor (TCR) activation during positive selection. Subsequent substrate analysis pinpointed protein phosphatase 2A (PP2A) as the enzyme responsible for the dephosphorylation changes in developing thymocytes. PP2A catalytic subunit α (Ppp2ca) deletion in the T cell lineage in Ppp2caflox/flox-Lck-Cre mice (PP2A cKO) displayed dysregulated dephosphorylation of apoptosis-related proteins in double-positive (DP) cells and caused substantially decreased numbers of DP CD4+ CD8+ cells. Increased levels of apoptosis in PP2A cKO DP cells were found to underlie aberrant thymocyte development. Finally, the defective thymocyte development in PP2A cKO mice could be rescued by either Bcl2 transgene expression or by p53 knockout. In summary, our work reveals an essential role of PP2A in promoting thymocyte development through the regulation of cell survival. Significance Ser/Thr phosphorylation is critical for T cell receptor signal transduction as well as cell survival/death regulation in developing thymocytes. In this work, we established a Ser/Thr phosphorylation profile during thymocytes selection. Substrate analysis revealed PP2A as the most important enzyme responsible for the dephosphorylation events, which was proved in the PP2A cKO model. Thymic-specific depletion of PP2A caused impaired thymocyte selection. The decrease of DP thymocytes upon PP2A cKO is accompanied by dysregulated dephosphorylation of apoptosis-related proteins and increased cell apoptosis, which could be rescued by Bcl2 transgene or p53 knockout. This studies the role of PP2A in thymocyte development and provides insights to understand T cell development through dephosphorylation regulation of apoptosis-related molecules.
Funding Information
  • National Natural Science Foundation of China (31770954)
  • National Natural Science Foundation of China (31530019)
  • National Natural Science Foundation of China (31500708)
  • China Postdoctoral Science Foundation (2015M580516)
  • China Postdoctoral Science Foundation (2016T90546)
  • National Natural Science Foundation of China (81570013)
  • National Natural Science Foundation of China (31700766)

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