Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation

Gaojian Lian; J. N.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 W.M. Fan; Ruoning Wang

doi:10.7554/eLife.36158

Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation

Gaojian Lian, J. N.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 W.M. Fan, Ruoning Wang

Research output: Contribution to journal › Article › peer-review

121 Scopus citations

Abstract

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.

Original language	English
Article number	e36158
Journal	eLife
Volume	7
DOIs	https://doi.org/10.7554/eLife.36158
State	Published - Sep 2018

Bibliographical note

Publisher Copyright:
© Lian et al.

Funding

Natural Science Foundation of Hunan Province This work was supported by R21AI117547 and 1R01AI114581 from National Institute of Health, V2014-001 from the V-Foundation and 128436-RSG-15-180-01-LIB from the American Cancer Society (RW), NIH K01AA025093 (YC), R24AA022057 (VV), the American Lebanese and Syrian Associated Charities (DG), and Natural Science Foundation of Hunan Province Grant 2018JJ2351(GL), NCI 1P01CA163223-01A1 and NIDDK 1U24DK097215-01A1 (TWMF), 130421-RSG-17-071-01-TBG from the American Cancer Society, R03 CA212802-01A1 (JY) and R21 AI113930 (YL). This work was supported by R21AI117547 and 1R01AI114581 from National Institute of Health, V2014-001 from the V-Foundation and 128436-RSG-15-180-01-LIB from the American Cancer Society (RW), K01AA025093 (YC), R24AA022057 (VV), the American Lebanese and Syrian Associated Charities (DG), and Natural Science Foundation of Hunan Province Grant 2018JJ2351(GL), NCI 1P01CA163223-01A1 and NIDDK 1U24DK097215-01A1 (TWMF), 130421-RSG-17-071-01-TBG from the American Cancer Society , R03 CA212802-01A1 (JY) and R21 AI113930 (YL).

Funders	Funder number
National Institutes of Health/National Institute of Environmental Health Sciences	V2014-001
Natural Science Foundation of Hunan Province, China	2018JJ2351
TWMF
V Foundation	128436-RSG-15-180-01-LIB
National Institutes of Health (NIH)	K01AA025093, R24AA022057, R21AI117547, 1R01AI114581
National Institutes of Health (NIH)
American Cancer Society-Michigan Cancer Research Fund	R03 CA212802-01A1, R21 AI113930
American Cancer Society-Michigan Cancer Research Fund
National Childhood Cancer Registry – National Cancer Institute	1P01CA163223-01A1
National Childhood Cancer Registry – National Cancer Institute
National Institute of Diabetes and Digestive and Kidney Diseases	U24DK097215, 130421-RSG-17-071-01-TBG
National Institute of Diabetes and Digestive and Kidney Diseases
American Lebanese Syrian Associated Charities

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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10.7554/eLife.36158

Cite this

Lian, G., Gnanaprakasam, J. N. R., Wang, T., Wu, R., Chen, X., Liu, L., Shen, Y., Yang, M., Yang, J., Chen, Y., Vasiliou, V., Cassel, T. A., Green, D. R., Liu, Y., Fan, T. W. M., & Wang, R. (2018). Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation. eLife, 7, Article e36158. https://doi.org/10.7554/eLife.36158

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title = "Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation",

abstract = "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.",

author = "Gaojian Lian and Gnanaprakasam, {J. N.Rashida} and Tingting Wang and Ruohan Wu and Xuyong Chen and Lingling Liu and Yuqing Shen and Mao Yang and Jun Yang and Ying Chen and Vasilis Vasiliou and Cassel, {Teresa A.} and Green, {Douglas R.} and Yusen Liu and Fan, {Teresa W.M.} and Ruoning Wang",

note = "Publisher Copyright: {\textcopyright} Lian et al.",

year = "2018",

month = sep,

doi = "10.7554/eLife.36158",

language = "English",

volume = "7",

}

Lian, G, Gnanaprakasam, JNR, 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, TWM & Wang, R 2018, 'Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation', eLife, vol. 7, e36158. https://doi.org/10.7554/eLife.36158

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T1 - Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation

AU - Lian, Gaojian

AU - Gnanaprakasam, J. N.Rashida

AU - Wang, Tingting

AU - Wu, Ruohan

AU - Chen, Xuyong

AU - Liu, Lingling

AU - Shen, Yuqing

AU - Yang, Mao

AU - Yang, Jun

AU - Chen, Ying

AU - Vasiliou, Vasilis

AU - Cassel, Teresa A.

AU - Green, Douglas R.

AU - Liu, Yusen

AU - Fan, Teresa W.M.

AU - Wang, Ruoning

PY - 2018/9

Y1 - 2018/9

N2 - 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.

AB - 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.

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Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation

Abstract

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