Tang Huayuan, Li Yali, Wang Shijia, Ji Jing, Zhu Xiangbin, Bao Yutong, Huang Can, Luo Ye, Huang Lei, Gao Yan, Wei Chaoliang, Liu Jie, Fang Xi, Sun Lu, Ouyang Kunfu
Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.
Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen 518132, China.
iScience. 2022 Apr 6;25(5):104209. doi: 10.1016/j.isci.2022.104209. eCollection 2022 May 20.
Emerging evidence shows that metabolic regulation may be a critical mechanism in B cell activation and function. As targets of several most widely used immunosuppressants, Ca signaling and calcineurin may play an important role in regulating B cell metabolism. Here, we demonstrate that IPR-mediated Ca signaling and calcineurin regulate B cell proliferation and survival by activating metabolic reprogramming in response to B cell receptor (BCR) stimulation. Both IPR-triple-knockout (IPR-TKO) and calcineurin inhibition dramatically suppress the metabolic switch in oxidative phosphorylation and glycolysis of stimulated B cells through regulation of glucose uptake, glycolytic enzyme expression, and mitochondrial remodeling, leading to impaired cell-cycle entry and survival. In addition, IPR-Ca acts as a master regulator of the calcineurin-MEF2C-Myc pathway in driving B cell metabolic adaptations. As genetic defects of IPRs were recently identified as a new class of inborn errors of immunity, these results have important implications for understanding the pathogenesis of such diseases.
新出现的证据表明，代谢调节可能是B细胞活化和功能的关键机制。作为几种最广泛使用的免疫抑制剂的作用靶点，钙信号和钙调神经磷酸酶可能在调节B细胞代谢中发挥重要作用。在此，我们证明，IPR介导的钙信号和钙调神经磷酸酶通过响应B细胞受体（BCR）刺激激活代谢重编程来调节B细胞增殖和存活。IPR三敲除（IPR-TKO）和钙调神经磷酸酶抑制均通过调节葡萄糖摄取、糖酵解酶表达和线粒体重塑，显著抑制受刺激B细胞氧化磷酸化和糖酵解中的代谢转换，导致细胞周期进入和存活受损。此外，IPR-Ca在驱动B细胞代谢适应过程中作为钙调神经磷酸酶-MEF2C-Myc途径的主要调节因子。由于最近发现IPR的基因缺陷是一类新的先天性免疫缺陷病，这些结果对理解此类疾病的发病机制具有重要意义。
