Orai3 and Orai1 mediate CRAC channel function and metabolic reprogramming in B cells

The essential role of store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ (CRAC) channels in T cells is well established. In contrast, the contribution of individual Orai isoforms to SOCE and their downstream signaling functions in B cells are poorly understood. Here, we demonstrate changes in the expression of Orai isoforms in response to B cell activation. We show that both Orai3 and Orai1 mediate native CRAC channels in B cells. The combined loss of Orai1 and Orai3, but not Orai3 alone, impairs SOCE, proliferation and survival, nuclear factor of activated T cells (NFAT) activation, mitochondrial respiration, glycolysis, and the metabolic reprogramming of primary B cells in response to antigenic stimulation. Nevertheless, the combined deletion of Orai1 and Orai3 in B cells did not compromise humoral immunity to influenza A virus infection in mice, suggesting that other in vivo co-stimulatory signals can overcome the requirement of BCR-mediated CRAC channel function in B cells. Our results shed important new light on the physiological roles of Orai1 and Orai3 proteins in SOCE and the effector functions of B lymphocytes.

Automated summary

This study reveals that Orai3 and Orai1 mediate native CRAC channels in B cells during activation, and the combined loss of both isoforms impairs various functions in B cells, including SOCE, proliferation, survival, NFAT activation, mitochondrial respiration, glycolysis, and metabolic reprogramming. However, the deletion of Orai1 and Orai3 does not affect humoral immunity to influenza A virus infection in mice, suggesting the presence of other co-stimulatory signals that compensate for the requirement of BCR-mediated CRAC channel function in B cells. These findings provide important insights into the physiological roles of Orai1 and Orai3 proteins in SOCE and effector functions of B lymphocytes.