Yazicioglu Yavuz F, Marin Eros, Andrew Hana F, Bentkowska Karolina, Johnstone Julia C, Mitchell Robert, Wong Zhi Yi, Zec Kristina, Fergusson Joannah, Borsa Mariana, Raza Iwan G A, Attar Moustafa, Ali Mohammad, Kronsteiner Barbara, Furlani Izadora L, MacRae James I, Devine Michael J, Coles Mark, Buckley Christopher D, Dunachie Susanna J, Clarke Alexander J
Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, UK.
Sci Immunol. 2024 Dec 13;9(102):eadl4613. doi: 10.1126/sciimmunol.adl4613.
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 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.
生发中心（GC）B细胞的快速增殖需要代谢重编程以满足能量需求，但这些代谢过程却知之甚少。通过整合GC B细胞的代谢组学和转录组学分析，我们发现天冬酰胺（Asn）代谢高度上调且对B细胞功能至关重要。通过整合应激反应传感器GCN2，B细胞活化后天冬酰胺合成酶（ASNS）被上调。在低Asn条件下，B细胞中ASNS的条件性缺失会损害细胞存活和增殖。用天冬酰胺酶去除环境中的Asn或饮食限制会损害GC反应，影响亲和力成熟以及对流感感染的体液反应。此外，对Asn缺失的代谢适应需要ASNS，并且氧化磷酸化、线粒体稳态和核苷酸合成对Asn剥夺特别敏感。这些发现表明，Asn代谢是B细胞功能和GC稳态的关键调节因子。
