2. Academic Validation
  3. Glucose-1-phosphate promotes compartmentalization of glycogen with the pentose phosphate pathway in CD8+ memory T cells

Glucose-1-phosphate promotes compartmentalization of glycogen with the pentose phosphate pathway in CD8+ memory T cells

  • Mol Cell. 2025 Jul 3;85(13):2535-2549.e10. doi: 10.1016/j.molcel.2025.05.019.
Yabo Zhou 1,  Chaoying Zhang 1,  Lina He 1,  Youli Kang 1,  Dianheng Wang 1,  Shujing Wang 1,  Zheng Ling 1,  Jie Chen 1,  Nannan Zhou 1,  Li Zhou 1,  Zhenfeng Wang 1,  Chaoqi Zhang 2,  Ke Tang 3,  Huafeng Zhang 4,  Jingwei Ma 5,  Bo Qin 6,  Sheng Cui 6,  Jiadi Lv 1,  Bo Huang 7
Affiliations

Affiliations

  • 1 Department of Immunology & State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing 100005, China.
  • 2 Department of Immunology & State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing 100005, China; Department of Thoracic Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing 100021, China.
  • 3 Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China.
  • 4 Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China.
  • 5 Department of Immunology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China.
  • 6 Key Laboratory of Pathogen Infection Prevention and Control (Ministry of Education), National Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 102629, China.
  • 7 Department of Immunology & State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing 100005, China; Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China. Electronic address: tjhuangbo@hotmail.com.
PMID: 40499549 DOI: 10.1016/j.molcel.2025.05.019
Abstract

Glucose-6-phosphate (G6P) is a key metabolic molecule that regulates Reactive Oxygen Species (ROS) homeostasis by initiating the pentose phosphate pathway (PPP) to generate nicotinamide adenine dinucleotide phosohate (NADPH) that converts hydrogen peroxide (H2O2) to water by providing hydrogen. While both glucose phosphorylation and glycogenolysis result in G6P production, here we show that G6P derived from glycogenolysis, rather than glucose phosphorylation, flows to PPP for ROS clearance in CD8+ memory T (Tm) cells and inflammatory macrophages. Mechanistically, glycogenolysis-produced glucose-1-phosphate (G1P) allosterically induces G6P dehydrogenase (G6PD) binding to glycogen, which together undergo liquid-liquid phase separation (LLPS) and recruit PPP Enzymes, resulting in a compartmentalized reaction cascade. Based on mechanistic elucidation, we demonstrated that G1P can act as an antitumor immunotherapeutic agent by modulating memory fitness and maintenance of tumor-reactive CD8+ T cells in mice. These findings revealed an unusual function of glycogen metabolism, which is of paramount importance in the regulation of PPP and redox homeostasis in cells.

Keywords

CD8(+) T(m); G1P; G6PD; LLPS; PPP; ROS; compartmentalization; glycogen.

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