Advanced Science (May 2024)
Urolithin A Hijacks ERK1/2‐ULK1 Cascade to Improve CD8+ T Cell Fitness for Antitumor Immunity
- Shuaiya Ma,
- Qi Wu,
- Wenxian Wu,
- Ye Tian,
- Jie Zhang,
- Chaojia Chen,
- Xue Sheng,
- Fangcheng Zhao,
- Lu Ding,
- Taixia Wang,
- Laixi Zhao,
- Yuying Xie,
- Yongxiang Wang,
- Xuetian Yue,
- Zhuanchang Wu,
- Jian Wei,
- Kun Zhang,
- Xiaohong Liang,
- Lifen Gao,
- Hongyan Wang,
- Guihua Wang,
- Chunyang Li,
- Chunhong Ma
Affiliations
- Shuaiya Ma
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine Shandong University Jinan Shandong 250012 P. R. China
- Qi Wu
- GI Cancer Research Institute Tongji Hospital Huazhong University of Science and Technology Wuhan Hubei 430074 P. R. China
- Wenxian Wu
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine Shandong University Jinan Shandong 250012 P. R. China
- Ye Tian
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine Shandong University Jinan Shandong 250012 P. R. China
- Jie Zhang
- Advanced Medical Research Institute Cheeloo College of Medicine Shandong University Jinan Shandong 250012 P. R. China
- Chaojia Chen
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine Shandong University Jinan Shandong 250012 P. R. China
- Xue Sheng
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine Shandong University Jinan Shandong 250012 P. R. China
- Fangcheng Zhao
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine Shandong University Jinan Shandong 250012 P. R. China
- Lu Ding
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine Shandong University Jinan Shandong 250012 P. R. China
- Taixia Wang
- Central Laboratory Tongji University School of Medicine Tongji University Shanghai 200072 P. R. China
- Laixi Zhao
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine Shandong University Jinan Shandong 250012 P. R. China
- Yuying Xie
- Guangdong Key Laboratory of Age‐Related Cardiac and Cerebral Disease Department of Neurology Affiliated Hospital of Guangdong Medical University Zhanjiang Guangdong 524001 P. R. China
- Yongxiang Wang
- Guangdong Key Laboratory of Age‐Related Cardiac and Cerebral Disease Department of Neurology Affiliated Hospital of Guangdong Medical University Zhanjiang Guangdong 524001 P. R. China
- Xuetian Yue
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Cell Biology School of Basic Medical Sciences Cheeloo College of Medicine Shandong University Jinan Shandong 250012 P. R. China
- Zhuanchang Wu
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine Shandong University Jinan Shandong 250012 P. R. China
- Jian Wei
- Department of Physiology School of Basic Medical Sciences Shandong University Jinan 250012 P. R. China
- Kun Zhang
- Central Laboratory Tongji University School of Medicine Tongji University Shanghai 200072 P. R. China
- Xiaohong Liang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine Shandong University Jinan Shandong 250012 P. R. China
- Lifen Gao
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine Shandong University Jinan Shandong 250012 P. R. China
- Hongyan Wang
- State Key Laboratory of Cell Biology Shanghai Institute of Biochemistry and Cell Biology Center for Excellence in Molecular Cell Science Chinese Academy of Sciences University of Chinese Academy of Sciences Shanghai 200031 P. R. China
- Guihua Wang
- GI Cancer Research Institute Tongji Hospital Huazhong University of Science and Technology Wuhan Hubei 430074 P. R. China
- Chunyang Li
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Histology and Embryology School of Basic Medical Sciences Cheeloo College of Medicine Shandong University Jinan Shandong 250012 P. R. China
- Chunhong Ma
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine Shandong University Jinan Shandong 250012 P. R. China
- DOI
- https://doi.org/10.1002/advs.202310065
- Journal volume & issue
-
Vol. 11,
no. 18
pp. n/a – n/a
Abstract
Abstract According to the latest evidence, the microbial metabolite Urolithin A (UA), known for its role in promoting cellular health, modulates CD8+ T cell‐mediated antitumor activity. However, the direct target protein of UA and its underlying mechanism remains unclear. Here, this research identifies ERK1/2 as the specific target crucial for UA‐mediated CD8+ T cell activation. Even at low doses, UA markedly enhances the persistence and effector functions of primary CD8+ cytotoxic T lymphocytes (CTLs) and human chimeric antigen receptor (CAR) T cells both in vitro and in vivo. Mechanistically, UA interacts directly with ERK1/2 kinases, enhancing their activation and subsequently facilitating T cell activation by engaging ULK1. The UA‐ERK1/2‐ULK1 axis promotes autophagic flux in CD8+ CTLs, enhancing cellular metabolism and maintaining reactive oxygen species (ROS) levels, as evidenced by increased oxygen consumption and extracellular acidification rates. UA‐treated CD8+ CTLs also display elevated ATP levels and enhanced spare respiratory capacity. Overall, UA activates ERK1/2, inducing autophagy and metabolic adaptation, showcasing its potential in tumor immunotherapy and interventions for diseases involving ERKs.
Keywords
