PMID- 38215751 OWN - NLM STAT- MEDLINE DCOM- 20240219 LR - 20240219 IS - 1097-4164 (Electronic) IS - 1097-2765 (Linking) VI - 84 IP - 4 DP - 2024 Feb 15 TI - A GAPDH serotonylation system couples CD8(+) T cell glycolytic metabolism to antitumor immunity. PG - 760-775.e7 LID - S1097-2765(23)01034-1 [pii] LID - 10.1016/j.molcel.2023.12.015 [doi] AB - 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. CI - Copyright (c) 2023 Elsevier Inc. All rights reserved. FAU - Wang, Xu AU - Wang X AD - Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, P.R. China. Electronic address: jsdxwx@126.com. FAU - Fu, Sheng-Qiao AU - Fu SQ AD - Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, P.R. China. FAU - Yuan, Xiao AU - Yuan X AD - Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, P.R. China. FAU - Yu, Feng AU - Yu F AD - School of Life Sciences, Jiangsu University, Zhenjiang 212013, P.R. China. FAU - Ji, Qian AU - Ji Q AD - Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, P.R. China. FAU - Tang, Hao-Wen AU - Tang HW AD - Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, P.R. China. FAU - Li, Rong-Kun AU - Li RK AD - Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, P.R. China. FAU - Huang, Shan AU - Huang S AD - 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. FAU - Huang, Pei-Qi AU - Huang PQ AD - 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. FAU - Qin, Wei-Ting AU - Qin WT AD - 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. FAU - Zuo, Hao AU - Zuo H AD - School of Life Sciences, Jiangsu University, Zhenjiang 212013, P.R. China. FAU - Du, Chang AU - Du C AD - 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. FAU - Yao, Lin-Li AU - Yao LL AD - 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. FAU - Li, Hui AU - Li H AD - 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. FAU - Li, Jun AU - Li J AD - 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. FAU - Li, Dong-Xue AU - Li DX AD - 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. FAU - Yang, Yan AU - Yang Y AD - 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. FAU - Xiao, Shu-Yu AU - Xiao SY AD - 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. FAU - Tulamaiti, Aziguli AU - Tulamaiti A AD - 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. FAU - Wang, Xue-Feng AU - Wang XF AD - Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, P.R. China. FAU - Dai, Chun-Hua AU - Dai CH AD - Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, P.R. China. FAU - Zhang, Xu AU - Zhang X AD - 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. FAU - Jiang, Shu-Heng AU - Jiang SH AD - 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. FAU - Hu, Li-Peng AU - Hu LP AD - 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. FAU - Zhang, Xue-Li AU - Zhang XL AD - 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. FAU - Zhang, Zhi-Gang AU - Zhang ZG AD - 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. LA - eng PT - Journal Article DEP - 20240111 PL - United States TA - Mol Cell JT - Molecular cell JID - 9802571 RN - 333DO1RDJY (Serotonin) SB - IM MH - *CD8-Positive T-Lymphocytes/metabolism MH - *Serotonin/metabolism/pharmacology MH - Protein Processing, Post-Translational MH - Signal Transduction OTO - NOTNLM OT - 5-HT OT - CD8(+) T cell OT - GAPDH OT - glycolysis OT - post-translational modification OT - serotonin OT - serotonylation OT - tumor immunity COIS- Declaration of interests The authors declare no competing interests. EDAT- 2024/01/13 00:42 MHDA- 2024/02/19 06:42 CRDT- 2024/01/12 18:42 PHST- 2023/03/06 00:00 [received] PHST- 2023/10/04 00:00 [revised] PHST- 2023/12/12 00:00 [accepted] PHST- 2024/02/19 06:42 [medline] PHST- 2024/01/13 00:42 [pubmed] PHST- 2024/01/12 18:42 [entrez] AID - S1097-2765(23)01034-1 [pii] AID - 10.1016/j.molcel.2023.12.015 [doi] PST - ppublish SO - Mol Cell. 2024 Feb 15;84(4):760-775.e7. doi: 10.1016/j.molcel.2023.12.015. Epub 2024 Jan 11.