IP3R-mediated Ca2+ signaling controls B cell proliferation through metabolic reprogramming
Huayuan Tang,
Yali Li,
Shijia Wang,
Jing Ji,
Xiangbin Zhu,
Yutong Bao,
Can Huang,
Ye Luo,
Lei Huang,
Yan Gao,
Chaoliang Wei,
Jie Liu,
Xi Fang,
Lu Sun,
Kunfu Ouyang
Affiliations
Huayuan Tang
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; Corresponding author
Yali Li
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
Shijia Wang
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
Jing Ji
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
Xiangbin Zhu
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
Yutong Bao
Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
Can Huang
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
Ye Luo
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
Lei Huang
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
Yan Gao
Department of Cardiovascular Medicine, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen Shekou People’s Hospital, Shenzhen, China
Chaoliang Wei
Department of Pathophysiology, School of Medicine, Shenzhen University, Shenzhen, China
Jie Liu
Department of Pathophysiology, School of Medicine, Shenzhen University, Shenzhen, China
Xi Fang
Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
Lu Sun
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; Corresponding author
Kunfu Ouyang
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; Corresponding author
Summary: 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, Ca2+ signaling and calcineurin may play an important role in regulating B cell metabolism. Here, we demonstrate that IP3R-mediated Ca2+ signaling and calcineurin regulate B cell proliferation and survival by activating metabolic reprogramming in response to B cell receptor (BCR) stimulation. Both IP3R-triple-knockout (IP3R-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, IP3R-Ca2+ acts as a master regulator of the calcineurin-MEF2C-Myc pathway in driving B cell metabolic adaptations. As genetic defects of IP3Rs were recently identified as a new class of inborn errors of immunity, these results have important implications for understanding the pathogenesis of such diseases.
