Glut3 promotes cellular O-GlcNAcylation as a distinctive tumorsupportive feature in Treg cells  

作　　者：Amit Sharma Garima Sharma Zhen Gao Ke Li Mutong Li Menglin Wu Chan Johng Kim Yingjia Chen Anupam Gautam Hong Bae Choi Jin Kim Jung-Myun Kwak Sin Man Lam Guanghou Shui Sandip Paul Yongqiang Feng Keunsoo Kang Sin-Hyeog Im Dipayan Rudra 

机构地区：[1]Department of Life Sciences,Pohang University of Science and Technology(POSTECH),Pohang,37673,Republic of Korea [2]Innovation Research Center for Biofuture Technology(B-IRC),Pohang University of Science and Technology(POSTECH),Pohang,37673,Republic of Korea [3]ImmmunoBiome Inc,Pohang,37673,Republic of Korea [4]School of Life Science&Technology,ShanghaiTech University,Shanghai,201210,China [5]Department of Biochemistry,University of Washington,Seattle,WA,98195,USA [6]Department of Immunology,St.Jude Children’s Research Hospital,Memphis,TN,38105,USA [7]Institute for Bioinformatics and Medical Informatics,University of Tübingen,Sand 14,Tübingen,72076,Germany [8]International Max Planck Research School“From Molecules to Organisms”,Max Planck Institute for Biology Tübingen,Max-Planck-Ring 5,Tübingen,72076,Germany [9]Daehang Hospital,Seoul,06699,Republic of Korea [10]Department of Surgery,Korea University College of Medicine,Seoul,02841,Republic of Korea [11]State Key Laboratory of Molecular Developmental Biology,Institute of Genetics and Developmental Biology Chinese Academy of Sciences,Beijing,100101,China [12]Lipidall Technologies Company Limited,Changzhou,213022,Jiangsu Province,China [13]University of Chinese Academy of Sciences,Beijing,100101,China [14]Center for Health Science and Technology,JIS Institute of Advanced Studies and Research,JIS University,Kolkata,700091,India [15]Department of Microbiology,College of Natural Sciences,Dankook University,Cheonan,31116,Republic of Korea [16]Institute for Convergence Research and Education in Advanced Technology,Yonsei University,Seoul,03722,Republic of Korea

出　　处：《Cellular & Molecular Immunology》2024年第12期1474-1490,共17页中国免疫学杂志(英文版)

基　　金：YC was financially supported by the Dissertation Completion Award of the University of Georgia and American Lebanese Syrian Associated Charities(ALSAC)at St.Jude Children’s Research Hospital;AG acknowledges support by the High Performance and Cloud Computing Group at the Zentrum für Datenverarbeitung of the University of Tübingen,the state of Baden-Württemberg through bwHPC and the German Research Foundation(DFG)through grant no INST 37/935-1 FUGG,and the de.NBI Cloud within the German Network for Bioinformatics Infrastructure(de.NBI)and ELIXIR-DE(Forschungszentrum Jülich and W-de.NBI-001,W-de.NBI-004,W-de.NBI-008,W-de.NBI-010,W-de.NBI-013,W-de.NBI-014,W-de.NBI-016,W-de.NBI-022)for supporting the computational analysis carried out in this work.AS was supported by BrainKorea21 Plus scholarship from the National Research Foundation of Korea(NRF);This research,in part,was supported by the Basic Science Research Program(grant#4.24643.01)funded by the Ministry of Education,Korea,and NRF grants#RS-2023-00260454(AS)and RS-2024-00345575(SHI)funded by the Korea Ministry of Science and ICT(MSIT);DR is recipient of National Natural Science Foundation of China grant#32470980.

摘　　要：Regulatory T cells(Tregs)establish dominant immune tolerance but obstruct tumor immune surveillance,warranting context-specific mechanistic insights into the functions of tumor-infiltrating Tregs(TIL-Tregs).We show that enhanced posttranslational O-linked N-acetylglucosamine modification(O-GlcNAcylation)of cellular factors is a molecular feature that promotes a tumor-specific gene expression signature and distinguishes TIL-Tregs from their systemic counterparts.We found that altered glucose utilization through the glucose transporter Glut3 is a major facilitator of this process.Treg-specific deletion of Glut3 abrogates tumor immune tolerance,while steady-state immune homeostasis remains largely unaffected in mice.Furthermore,by employing mouse tumor models and human clinical data,we identified the NF-κB subunit c-Rel as one such factor that,through Glut3-dependent O-GlcNAcylation,functionally orchestrates gene expression in Tregs at tumor sites.Together,these results not only identify immunometabolic alterations and molecular events contributing to fundamental aspects of Treg biology,specifically at tumor sites but also reveal tumor-specific cellular properties that can aid in the development of Treg-targeted cancer immunotherapies.

关 键 词：Regulatory T cells TREG GLUT3 O-GLCNACYLATION Treg metabolism 

分 类 号：R730.5[医药卫生—肿瘤]