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Abstract
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.
Highlights
T cell development depends primarily on glucose metabolism and glycolysis has been shown to play a vital role in the DN3–DN4 transition (Brand and Hermfisse, 1997; Sandy et al, 2012; Buck et al, 2015)
We show that Sin1, via mammalian target of rapamycin complex 2 (mTORC2), promotes double negative (DN) thymocyte proliferation through augmenting the transcriptional level of PKM2, a key enzyme for the final rate-limiting step of glycolysis by catalyzing the transfer of phosphoenolpyruvate (PEP) to pyruvate
In vitro and in vivo treatments with PKM2 activator confirm that PKM2 is responsible for mediating the Sin1–mTORC2 signaling in thymocyte development
Summary
T cell development depends primarily on glucose metabolism and glycolysis has been shown to play a vital role in the DN3–DN4 transition (Brand and Hermfisse, 1997; Sandy et al, 2012; Buck et al, 2015). Specific extracellular signals have been shown to participate in the regulation of intracellular glucose metabolism during thymocyte development and the PI3K/AKT signaling cascade has been shown to be one of the most important regulators for the glycolytic metabolism to trigger early T cell development (Powell and Delgoffe, 2010; Zeng and Chi, 2013). The PI3K/AKT signaling cascade mediates cellular metabolism and growth through at least two well defined but distinct mammalian target of rapamycin (mTOR) complexes, mTORC1 and mTORC2, to control T cell development, activation and Received June 28, 2018.
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