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

doi:10.1016/j.isci.2022.104209

IP₃R-mediated Ca²⁺ signaling controls B cell proliferation through metabolic reprogramming

iScience. 2022 Apr 6;25(5):104209. doi: 10.1016/j.isci.2022.104209. eCollection 2022 May 20.

Authors

Huayuan Tang^{1

2}, Yali Li^{1

2}, Shijia Wang¹, Jing Ji¹, Xiangbin Zhu¹, Yutong Bao³, Can Huang¹, Ye Luo¹, Lei Huang¹, Yan Gao⁴, Chaoliang Wei⁵, Jie Liu⁵, Xi Fang³, Lu Sun¹, Kunfu Ouyang¹

Affiliations

¹ 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.
² Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen 518132, China.
³ Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA.
⁴ Department of Cardiovascular Medicine, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen Shekou People's Hospital, Shenzhen, China.
⁵ Department of Pathophysiology, School of Medicine, Shenzhen University, Shenzhen, China.

Abstract

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.

Keywords: Cell biology; Immune response; Immunology.