Suppression of calcium release from inositol 1,4,5-trisphosphate-sensitive stores mediates the anti-apoptotic function of nuclear factor-κB

The activation of the transcription factor nuclear factor-κB (NF-κB) by growth factors, cytokines, and cellular stress can prevent apoptosis, but the underlying mechanism is unknown. Here we provide evidence for an action of NF-κB on calcium signaling that accounts for its anti-apoptotic function. Embryonic fibroblasts lacking the transactivating subunit of NF-κB RelA (p65) exhibit enhanced inositol 1,4,5-trisphosphate (IP₃) receptor-mediated calcium release and increased sensitivity to apoptosis, which are restored upon re-expression of RelA. The size of the endoplasmic reticulum (ER) calcium pool and the number of IP₃ receptors per cell are decreased in response to stimuli that activate NF-κB and are increased when NF-κB activity is suppressed. The selective antagonism of IP₃ receptors blocks apoptosis in RelA-deficient cells, whereas activation of NF-κB in normal cells leads to decreased levels of the type 1 IP₃ receptor and decreased calcium release. Overexpression of Bcl-2 normalizes ER calcium homeostasis and prevents calcium-mediated apoptosis in RelA-deficient cells. These findings establish an ER calcium channel as a pivotal target for NF-κB-mediated cell survival signaling.