IPR-mediated Ca signaling controls B cell proliferation through metabolic reprogramming.

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.