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Protein Phosphatase 2A Has an Essential Role in Promoting Thymocyte Survival During Selection

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Protein Phosphatase 2A Has an Essential Role in Promoting Thymocyte Survival During Selection Protein phosphatase 2A has an essential role in promoting thymocyte survival during selection Mingzhu Zhenga,b,1, Dan Lia,b,1, Zhishan Zhaoa,b, Dmytro Shytikova,b, Qin Xua,b, Xuexiao Jina,b,c, Jingjing Lianga,b, Jun Loua,b, Songquan Wud, Lie Wanga,HuHue, Yiting Zhouf,g, Xiang Gaoh,2, and Linrong Lua,b,c,g,i,2 aInstitute of Immunology, and Department of Dermatology and Rheumatology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310058 Hangzhou, P. R. China; bProgram in Molecular and Cellular Biology, Zhejiang University School of Medicine, 310058 Hangzhou, P. R. China; cZhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, 310058 Hangzhou, P. R. China; dMedical College of Lishui University, Lishui, 323000 Zhejiang, China; eDepartment of Pathology and Pathophysiology, Zhejiang University School of Medicine, 310058 Hangzhou, P. R. China; fDepartment of Biochemistry and Molecular Biology, Zhejiang University School of Medicine, 310058 Hangzhou, P. R. China; gDr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, 310058 Hangzhou, P. R. China; hKey Laboratory of Model Animals for Disease Study of the Ministry of Education, Model Animal Research Center, Nanjing University, 210061 Nanjing, P. R. China; and iInnovation Center for Cell Signaling Technology Network, Zhejiang University School of Medicine, 310058 Hangzhou, P. R. China Edited by Arthur Weiss, University of California, San Francisco, CA, and approved May 7, 2019 (received for review December 12, 2018) The development of thymocytes to mature T cells in the thymus is as Ser/Thr phosphorylation of prosurvival proteins is also vital for tightly controlled by cellular selection, in which only a small thymocyte survival. For example, phosphorylation of different sites fraction of thymocytes equipped with proper quality of TCRs in Mcl-1 play opposing roles in thymocyte survival, while changes progress to maturation. It is pivotal to protect the survival of the in Ser/Thr phosphorylation status of the proapoptotic protein Bim few T cells, which pass the selection. However, the signaling have also been implicated in the decision of cell survival or cell events, which safeguard the cell survival in thymus, are not totally death during negative selection (7, 8). ERK activation, which is understood. In this study, protein Ser/Thr phosphorylation in also marked by Ser/Thr phosphorylation, has been shown to be thymocytes undergoing positive selection is profiled by mass essential for the positive selection of thymocytes (9). However, spectrometry. The results revealed large numbers of dephosphor- despite these findings, the landscape of Ser/Thr phosphorylation ylation changes upon T cell receptor (TCR) activation during during thymocyte selection has not been completely characterized. positive selection. Subsequent substrate analysis pinpointed pro- In contrast to Ser/Thr phosphorylation, which is governed by a INFLAMMATION tein phosphatase 2A (PP2A) as the enzyme responsible for the plethora of kinases, dephosphorylation of proteins is regulated IMMUNOLOGY AND dephosphorylation changes in developing thymocytes. PP2A catalytic by only a handful of phosphatases. Many studies have suggested subunit α (Ppp2ca) deletion in the T cell lineage in Ppp2caflox/flox-Lck-Cre that phosphatases sensitive to the inhibition by okadaic acid are mice (PP2A cKO) displayed dysregulated dephosphorylation of involved in the regulation of T cell signaling and activation. apoptosis-related proteins in double-positive (DP) cells and caused However, the role of threonine phosphatase PP2A, one of the substantially decreased numbers of DP CD4+ CD8+ cells. Increased most important targets of okadaic acid, in thymocyte selection levels of apoptosis in PP2A cKO DP cells were found to underlie remains unclear. PP2A consists of three subunits: A (scaffold aberrant thymocyte development. Finally, the defective thymo- subunit), B (regulatory subunit), and C (catalytic subunit). PP2A α β cyte development in PP2A cKO mice could be rescued by either C subunit isoforms, (Ppp2ca) and (Ppp2cb), share a 97% Bcl2 transgene expression or by p53 knockout. In summary, our identity in their amino acid sequence. However, Ppp2ca is 10 work reveals an essential role of PP2A in promoting thymocyte development through the regulation of cell survival. Significance thymocyte selection | PP2A | apoptosis Ser/Thr phosphorylation is critical for T cell receptor signal trans- duction as well as cell survival/death regulation in developing lymphocytes are the major form of adaptive immune cells thymocytes. In this work, we established a Ser/Thr phosphoryla- Tthat target pathogens (1, 2). T cell precursors originate in the tion profile during thymocytes selection. Substrate analysis bone marrow and then migrate to the thymus to initiate differ- revealed PP2A as the most important enzyme responsible for the – – entiation into mature T cells. In the thymus, CD4 CD8 double- dephosphorylation events, which was proved in the PP2A cKO negative (DN) thymocytes (which can be subcategorized as stages model. Thymic-specific depletion of PP2A caused impaired thy- DN1–DN4) acquire T cell receptor (TCR) expression through mocyte selection. The decrease of DP thymocytes upon PP2A cKO + + VDJ recombination and develop into CD4 CD8 double-positive is accompanied by dysregulated dephosphorylation of apoptosis- + + (DP) thymocytes, which subsequently give rise to CD4 or CD8 related proteins and increased cell apoptosis, which could be single-positive (SP) T cells. Two pivotal selection processes occur, rescued by Bcl2 transgene or p53 knockout. This studies the role namely positive selection and negative selection, and both serve as of PP2A in thymocyte development and provides insights to un- gatekeepers in the progress of DP T cells to the SP stage. Notably, derstand T cell development through dephosphorylation regula- only a small percentage of DP thymocytes survive through the tion of apoptosis-related molecules. selection process to become mature T cells bearing TCRs with suitable reactivity. Secure survival of the T cells which do pass Author contributions: M.Z., D.L., S.W., L.W., H.H., Y.Z., X.G., and L.L. designed research; M.Z., D.L., Z.Z., D.S., Q.X., X.J., J. Liang, and J. Lou performed research; M.Z., D.L., and L.L. selection is then of pivotal importance during thymic development. analyzed data; and M.Z., D.L., and L.L. wrote the paper. It has been shown that TCRs on the DP cell surface can bind The authors declare no conflict of interest. to self-peptide–major histocompatibility complex (MHC) com- plexes on thymic epithelial and dendritic cells, which provide This article is a PNAS Direct Submission. signals for thymocyte survival (3–5). Up-regulation of expression Published under the PNAS license. of survival-related proteins is one of the known mechanisms to 1M.Z. and D.L. contributed equally to this work. promote thymocyte survival in this context. Well-studied exam- 2To whom correspondence may be addressed. Email: [email protected] or ples include the Bcl-2 family prosurvival proteins Bcl-xL, whose [email protected]. stage-specific enrichment promotes the survival of DP thymocytes This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. (6). In addition to regulations at the level of gene expression, 1073/pnas.1821116116/-/DCSupplemental. further studies revealed that posttranslational modifications such www.pnas.org/cgi/doi/10.1073/pnas.1821116116 PNAS Latest Articles | 1of6 Downloaded by guest on October 4, 2021 times more abundant than Ppp2cb and has been demonstrated to Fig. S1A), RT-PCR (SI Appendix,Fig.S1C), and Western blot (SI play a dominant role in mouse cells (10). PP2A is able to de- Appendix,Fig.S1B) analysis all demonstrated the specific deletion + + − − phosphorylate a range of proteins such as Akt, p53, and c-Myc in of PP2Ac in CD4 CD8 DP thymocytes but not in CD4 CD8 DN different T cell types and plays a fundamental role in cell sur- thymocytes. Given that the absence of PP2A would directly affect vival, signal transduction, and proliferation (11). the dephosphorylation of its target proteins, we profiled Ser/Thr In this study, we established a profile of Ser/Thr phosphory- phosphorylation sites in PP2A cKO thymocytes using iTRAQ lation in developing thymocytes. Among the rates of protein phosphor-peptide analysis. The loss of PP2A caused significant dephosphorylation we identified, two of the top five are known phosphorylation status changes in 370 proteins in TCR-stimulated substrates of phosphatase PP2A (12, 13), suggesting a central thymocytes (Fig. 1B). As expected, TOP2A, which is a potential role of PP2A in this process. In T cell-specific PP2A-deficient + + PP2A target protein observed in T cells, no longer altered its mice, there is a dramatic decrease in levels of CD4 CD8 DP T cells, phosphorylation level upon TCR stimulation, while dephosphory- owing to an increased susceptibility to apoptosis. Furthermore, lation of another target protein Smarca4 was also less apparent. we found changes in phosphorylation of apoptosis-related pro- Among the top 35 proteins with increased phosphorylation levels of teins underlies the phenotype of PP2Ac-deficient thymocytes. more than 1.75-fold in PP2A cKO cells, six of them are related to Thus, our study reveals a critical role of PP2Ac in thymocyte cell survival (Fig. 1C, marked with red font, and Fig. 1D). Some of
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