Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation
Gaojian Lian,
JN Rashida Gnanaprakasam,
Tingting Wang,
Ruohan Wu,
Xuyong Chen,
Lingling Liu,
Yuqing Shen,
Mao Yang,
Jun Yang,
Ying Chen,
Vasilis Vasiliou,
Teresa A Cassel,
Douglas R Green,
Yusen Liu,
Teresa WM Fan,
Ruoning Wang
Affiliations
Gaojian Lian
Center for Childhood Cancer and Blood Diseases, Hematology, Oncology and BM, The Research Institute at Nationwide Children's Hospital, Ohio State University, Columbus, United States; Medical Research Center, University of South China, Hengyang, Hunan Province, China
Center for Childhood Cancer and Blood Diseases, Hematology, Oncology and BM, The Research Institute at Nationwide Children's Hospital, Ohio State University, Columbus, United States
Tingting Wang
Center for Childhood Cancer and Blood Diseases, Hematology, Oncology and BM, The Research Institute at Nationwide Children's Hospital, Ohio State University, Columbus, United States
Ruohan Wu
Center for Childhood Cancer and Blood Diseases, Hematology, Oncology and BM, The Research Institute at Nationwide Children's Hospital, Ohio State University, Columbus, United States
Xuyong Chen
Center for Childhood Cancer and Blood Diseases, Hematology, Oncology and BM, The Research Institute at Nationwide Children's Hospital, Ohio State University, Columbus, United States
Lingling Liu
Center for Childhood Cancer and Blood Diseases, Hematology, Oncology and BM, The Research Institute at Nationwide Children's Hospital, Ohio State University, Columbus, United States
Yuqing Shen
Center for Childhood Cancer and Blood Diseases, Hematology, Oncology and BM, The Research Institute at Nationwide Children's Hospital, Ohio State University, Columbus, United States
Mao Yang
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, United States
Jun Yang
Department of Surgery, St. Jude Children’s Research Hospital, Memphis, United States
Ying Chen
Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, United States
Vasilis Vasiliou
Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, United States
Teresa A Cassel
Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, United States; Markey Cancer Center, University of Kentucky, Lexington, United States; Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, United States
Douglas R Green
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, United States
Yusen Liu
Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Ohio State University, Columbus, Ohio, United States
Teresa WM Fan
Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, United States; Markey Cancer Center, University of Kentucky, Lexington, United States; Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, United States
Center for Childhood Cancer and Blood Diseases, Hematology, Oncology and BM, The Research Institute at Nationwide Children's Hospital, Ohio State University, Columbus, United States
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.
