. 2024 Feb 15;84(4):760-775.e7.

doi: 10.1016/j.molcel.2023.12.015. Epub 2024 Jan 11.

A GAPDH serotonylation system couples CD8⁺ T cell glycolytic metabolism to antitumor immunity

Xu Wang¹, Sheng-Qiao Fu², Xiao Yuan², Feng Yu³, Qian Ji², Hao-Wen Tang², Rong-Kun Li², Shan Huang⁴, Pei-Qi Huang⁴, Wei-Ting Qin⁴, Hao Zuo³, Chang Du⁴, Lin-Li Yao⁴, Hui Li⁴, Jun Li⁴, Dong-Xue Li⁴, Yan Yang⁴, Shu-Yu Xiao⁴, Aziguli Tulamaiti⁴, Xue-Feng Wang², Chun-Hua Dai², Xu Zhang⁵, Shu-Heng Jiang⁶, Li-Peng Hu⁷, Xue-Li Zhang⁸, Zhi-Gang Zhang⁹

Affiliations

¹ Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, P.R. China. Electronic address: jsdxwx@126.com.
² Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, P.R. China.
³ School of Life Sciences, Jiangsu University, Zhenjiang 212013, P.R. China.
⁴ State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China.
⁵ Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, P.R. China. Electronic address: xuzhang@ujs.edu.cn.
⁶ State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China. Electronic address: shjiang@shsci.org.
⁷ State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China. Electronic address: lphu@shsci.org.
⁸ State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China. Electronic address: xlzhang@shsci.org.
⁹ State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China. Electronic address: zzhang@shsci.org.

PMID: 38215751
DOI: 10.1016/j.molcel.2023.12.015

A GAPDH serotonylation system couples CD8⁺ T cell glycolytic metabolism to antitumor immunity

Xu Wang et al. Mol Cell. 2024.

. 2024 Feb 15;84(4):760-775.e7.

doi: 10.1016/j.molcel.2023.12.015. Epub 2024 Jan 11.

Authors

Affiliations

¹ Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, P.R. China. Electronic address: jsdxwx@126.com.
² Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, P.R. China.
³ School of Life Sciences, Jiangsu University, Zhenjiang 212013, P.R. China.
⁴ State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China.
⁵ Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, P.R. China. Electronic address: xuzhang@ujs.edu.cn.
⁶ State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China. Electronic address: shjiang@shsci.org.
⁷ State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China. Electronic address: lphu@shsci.org.
⁸ State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China. Electronic address: xlzhang@shsci.org.
⁹ State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China. Electronic address: zzhang@shsci.org.

PMID: 38215751
DOI: 10.1016/j.molcel.2023.12.015

Abstract

Apart from the canonical serotonin (5-hydroxytryptamine [5-HT])-receptor signaling transduction pattern, 5-HT-involved post-translational serotonylation has recently been noted. Here, we report a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serotonylation system that promotes the glycolytic metabolism and antitumor immune activity of CD8⁺ T cells. Tissue transglutaminase 2 (TGM2) transfers 5-HT to GAPDH glutamine 262 and catalyzes the serotonylation reaction. Serotonylation supports the cytoplasmic localization of GAPDH, which induces a glycolytic metabolic shift in CD8⁺ T cells and contributes to antitumor immunity. CD8⁺ T cells accumulate intracellular 5-HT for serotonylation through both synthesis by tryptophan hydroxylase 1 (TPH1) and uptake from the extracellular compartment via serotonin transporter (SERT). Monoamine oxidase A (MAOA) degrades 5-HT and acts as an intrinsic negative regulator of CD8⁺ T cells. The adoptive transfer of 5-HT-producing TPH1-overexpressing chimeric antigen receptor T (CAR-T) cells induced a robust antitumor response. Our findings expand the known range of neuroimmune interaction patterns by providing evidence of receptor-independent serotonylation post-translational modification.

Keywords: 5-HT; CD8(+) T cell; GAPDH; glycolysis; post-translational modification; serotonin; serotonylation; tumor immunity.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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A GAPDH serotonylation system couples CD8⁺ T cell glycolytic metabolism to antitumor immunity

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A GAPDH serotonylation system couples CD8⁺ T cell glycolytic metabolism to antitumor immunity

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