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

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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

Funding Information:
Natural Science Foundation of Hunan Province

Funding Information:
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).

Funding Information:
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).

Publisher Copyright:
© Lian et al.

ASJC Scopus subject areas

Neuroscience (all)
Biochemistry, Genetics and Molecular Biology (all)
Immunology and Microbiology (all)

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10.7554/eLife.36158

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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, [e36158]. https://doi.org/10.7554/eLife.36158

@article{e72c0c103ccd4bef89d9f63a1aaf9d51,

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 = "Funding Information: Natural Science Foundation of Hunan Province Funding Information: 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). Funding Information: 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). 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

TY - JOUR

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

N1 - Funding Information: Natural Science Foundation of Hunan Province Funding Information: 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). Funding Information: 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). Publisher Copyright: © Lian et al.

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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U2 - 10.7554/eLife.36158

DO - 10.7554/eLife.36158

M3 - Article

C2 - 30198844

AN - SCOPUS:85058401910

VL - 7

M1 - e36158

ER -

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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ASJC Scopus subject areas

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