iScience | VOL. 25
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IP3R-mediated Ca2+ signaling controls B cell proliferation through metabolic reprogramming

Publication Date May 1, 2022

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.

Concepts
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IP3R-mediated Ca2
Cell Metabolic Adaptations
Regulation Of Glucose Uptake
Glycolytic Enzyme Expression
B Cell Receptor
Mitochondrial Remodeling
Metabolic Reprogramming
Cell Proliferation
Critical Mechanism
Oxidative Phosphorylation

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