Metabolic regulation of T cell development by Sin1-mTORC2 is mediated by pyruvate kinase M2
| Autor: | Qiang Zou, Omotooke Arojo, Man Li, Ningbo Wu, Hongzhi Liu, Lei Chen, Xiaobo Liu, Bing Su, Xinxing Ouyang, Guojun Qu, Dou Liu, Yuheng Han, Hongxiang Sun |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Thyroid Hormones PPAR-γ Proto-Oncogene Proteins c-akt T cell T-Lymphocytes Mice Transgenic Mechanistic Target of Rapamycin Complex 2 PKM2 mTORC2 03 medical and health sciences Mediator Complex Subunit 1 Mice 0302 clinical medicine Genetics medicine Animals Glycolysis Molecular Biology thymocyte development Adaptor Proteins Signal Transducing Cell Proliferation Cell growth Chemistry TOR Serine-Threonine Kinases Membrane Proteins Cell Differentiation Cell Biology General Medicine Cell biology Thymocyte 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Original Article Sin1 Carrier Proteins metabolism Pyruvate kinase |
| Zdroj: | Journal of Molecular Cell Biology |
| ISSN: | 1759-4685 |
| Popis: | Glucose metabolism plays a key role in thymocyte development. The mammalian target of rapamycin complex 2 (mTORC2) is a critical regulator of cell growth and metabolism, but its role in early thymocyte development and metabolism has not been fully studied. We show here that genetic ablation of Sin1, an essential component of mTORC2, in T lineage cells results in severely impaired thymocyte development at the CD4−CD8− double negative (DN) stages but not at the CD4+CD8+ double positive (DP) or later stages. Notably, Sin1-deficient DN thymocytes show markedly reduced proliferation and glycolysis. Importantly, we discover that the M2 isoform of pyruvate kinase (PKM2) is a novel and crucial Sin1 effector in promoting DN thymocyte development and metabolism. At the molecular level, we show that Sin1–mTORC2 controls PKM2 expression through an AKT-dependent PPAR-γ nuclear translocation. Together, our study unravels a novel mTORC2−PPAR-γ−PKM2 pathway in immune-metabolic regulation of early thymocyte development. |
| Databáze: | OpenAIRE |
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