Yavuz F. Yazicioglu, Eros Marin, Hana F. Andrew, Karolina Bentkowska, Julia C. Johnstone, Robert Mitchell, Zhi Yi Wong, Kristina Zec, Joannah Fergusson, Mariana Borsa, Iwan G. A. Raza, Moustafa Attar, Mohammad Ali, Barbara Kronsteiner, Izadora L. Furlani, James I. MacRae, Michael J. Devine, Mark Coles, Christopher D. Buckley, Susanna J. Dunachie, Alexander J. Clarke
{"title":"Asparagine availability controls germinal center B cell homeostasis","authors":"Yavuz F. Yazicioglu, Eros Marin, Hana F. Andrew, Karolina Bentkowska, Julia C. Johnstone, Robert Mitchell, Zhi Yi Wong, Kristina Zec, Joannah Fergusson, Mariana Borsa, Iwan G. A. Raza, Moustafa Attar, Mohammad Ali, Barbara Kronsteiner, Izadora L. Furlani, James I. MacRae, Michael J. Devine, Mark Coles, Christopher D. Buckley, Susanna J. Dunachie, Alexander J. Clarke","doi":"10.1126/sciimmunol.adl4613","DOIUrl":null,"url":null,"abstract":"The rapid proliferation of germinal center (GC) B cells requires metabolic reprogramming to meet energy demands, yet these metabolic processes are poorly understood. By integrating metabolomic and transcriptomic profiling of GC B cells, we identified that asparagine (Asn) metabolism was highly up-regulated and essential for B cell function. Asparagine synthetase (ASNS) was up-regulated after B cell activation through the integrated stress response sensor GCN2. Conditional deletion of <jats:italic>Asns</jats:italic> in B cells impaired survival and proliferation in low Asn conditions. Removal of environmental Asn by asparaginase or dietary restriction compromised the GC reaction, impairing affinity maturation and the humoral response to influenza infection. Furthermore, metabolic adaptation to the absence of Asn required ASNS, and oxidative phosphorylation, mitochondrial homeostasis, and synthesis of nucleotides were particularly sensitive to Asn deprivation. These findings demonstrate that Asn metabolism acts as a key regulator of B cell function and GC homeostasis.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"233 1","pages":""},"PeriodicalIF":17.6000,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Immunology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1126/sciimmunol.adl4613","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
The rapid proliferation of germinal center (GC) B cells requires metabolic reprogramming to meet energy demands, yet these metabolic processes are poorly understood. By integrating metabolomic and transcriptomic profiling of GC B cells, we identified that asparagine (Asn) metabolism was highly up-regulated and essential for B cell function. Asparagine synthetase (ASNS) was up-regulated after B cell activation through the integrated stress response sensor GCN2. Conditional deletion of Asns in B cells impaired survival and proliferation in low Asn conditions. Removal of environmental Asn by asparaginase or dietary restriction compromised the GC reaction, impairing affinity maturation and the humoral response to influenza infection. Furthermore, metabolic adaptation to the absence of Asn required ASNS, and oxidative phosphorylation, mitochondrial homeostasis, and synthesis of nucleotides were particularly sensitive to Asn deprivation. These findings demonstrate that Asn metabolism acts as a key regulator of B cell function and GC homeostasis.
生殖中心(GC)B细胞的快速增殖需要进行代谢重编程以满足能量需求,但人们对这些代谢过程知之甚少。通过整合 GC B 细胞的代谢组学和转录组学图谱,我们发现天冬酰胺(Asn)代谢高度上调,并且对 B 细胞功能至关重要。天冬酰胺合成酶(ASNS)在 B 细胞激活后通过综合应激反应传感器 GCN2 上调。在低天冬酰胺条件下,B细胞中条件性缺失的天冬酰胺合成酶(ASNS)会影响其存活和增殖。通过天冬酰胺酶或饮食限制去除环境中的Asn会影响GC反应,损害亲和力成熟和对流感感染的体液反应。此外,新陈代谢对缺乏 Asn 的适应需要 ASNS,氧化磷酸化、线粒体平衡和核苷酸合成对 Asn 剥夺特别敏感。这些发现表明,Asn 代谢是 B 细胞功能和 GC 平衡的关键调节因子。
期刊介绍:
Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.