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

Elife. 2023 Feb 21:12:e84708. doi: 10.7554/eLife.84708.


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.

Keywords: B cells; CRAC channels; Orai1; Orai3; SOCE; biochemistry; cell biology; chemical biology; metabolism; mouse.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • B-Lymphocytes* / metabolism
  • Calcium / metabolism
  • Calcium Channels* / metabolism
  • Calcium Signaling / physiology
  • Mice
  • ORAI1 Protein* / genetics
  • ORAI1 Protein* / metabolism
  • Stromal Interaction Molecule 1 / genetics
  • Stromal Interaction Molecule 1 / metabolism


  • Calcium
  • Calcium Channels
  • ORAI1 Protein
  • Orai1 protein, mouse
  • Orai3 protein, mouse
  • Stromal Interaction Molecule 1