STIM- and Orai-mediated calcium entry controls NF-κB activity and function in lymphocytes

The central role of Ca²⁺ signaling in the development of functional immunity and tolerance is well established. These signals are initiated by antigen binding to cognate receptors on lymphocytes that trigger store operated Ca²⁺ entry (SOCE). The underlying mechanism of SOCE in lymphocytes involves TCR and BCR mediated activation of Stromal Interaction Molecule 1 and 2 (STIM1/2) molecules embedded in the ER membrane leading to their activation of Orai channels in the plasma membrane. STIM/Orai dependent Ca²⁺ signals guide key antigen induced lymphocyte development and function principally through direct regulation of Ca²⁺ dependent transcription factors. The role of Ca²⁺ signaling in NFAT activation and signaling is well known and has been studied extensively, but a wide appreciation and mechanistic understanding of how Ca²⁺ signals also shape the activation and specificity of NF-κB dependent gene expression has lagged. Here we discuss and interpret what is known about Ca²⁺ dependent mechanisms of NF-kB activation, including what is known and the gaps in our understanding of how these signals control lymphocyte development and function.