Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation.
Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation.
复制标题
作者：
Lian G;Gnanaprakasam JR;Wang T;Wu R;Chen X;Liu L;Shen Y;Yang M;Yang J;Chen Y;Vasiliou V;Cassel TA;Green DR;Liu Y;Fan TW;Wang R
在抗原刺激后，T淋巴细胞经历代谢的显著变化以满足增殖和分化的生物能量、生物合成和氧化还原需求。谷胱甘肽（GSH）在控制氧化还原平衡和细胞命运中起着至关重要的作用。虽然GSH可以从二硫代谷氨酸（GSSG）中回收，但抑制这种回收途径不会影响GSH含量和鼠T细胞命运。相比之下，通过删除谷氨酸-半胱氨酸连接酶（Gcl）的催化亚基（Gclc）或修饰亚基（Gclm）来抑制GSH的从头合成，抑制细胞内GSH，增加ROS，并影响T细胞分化。此外，GSH从头合成的抑制抑制了实验性自身免疫性脑脊髓炎（EAE）的病理进展。我们进一步揭示，谷氨酰胺提供GSH生物合成的必要前体。我们的研究结果表明，谷氨酰胺催化剂燃料从头合成的GSH和指导T细胞的谱系选择。
Upon antigen stimulation, T lymphocytes undergo dramatic changes in metabolism to fulfill the bioenergetic, biosynthetic and redox demands of proliferation and differentiation. Glutathione (GSH) plays an essential role in controlling redox balance and cell fate. While GSH can be recycled from Glutathione disulfide (GSSG), the inhibition of this recycling pathway does not impact GSH content and murine T cell fate. By contrast, the inhibition of the de novo synthesis of GSH, by deleting either the catalytic (Gclc) or the modifier (Gclm) subunit of glutamate–cysteine ligase (Gcl), dampens intracellular GSH, increases ROS, and impact T cell differentiation. Moreover, the inhibition of GSH de novo synthesis dampened the pathological progression of experimental autoimmune encephalomyelitis (EAE). We further reveal that glutamine provides essential precursors for GSH biosynthesis. Our findings suggest that glutamine catabolism fuels de novo synthesis of GSH and directs the lineage choice in T cells.