Mitochondria to nucleus stress signaling: a distinctive mechanism of NFκB/Rel activation through calcineurin-mediated inactivation of IκBβ

Mitochondrial genetic and metabolic stress causes activation of calcineurin (Cn), NFAT, ATF2, and NFκB/Rel factors, which collectively alter the expression of an array of nuclear genes. We demonstrate here that mitochondrial stress–induced activation of NFκB/Rel factors involves inactivation of IκBβ through Cn-mediated dephosphorylation. Phosphorylated IκBβ is a substrate for Cn phosphatase, which was inhibited by FK506 and RII peptide. Chemical cross-linking and coimmunoprecipitation show that NFκB/Rel factor–bound IκBβ forms a ternary complex with Cn under in vitro and in vivo conditions that was sensitive to FK506. Results show that phosphorylation at S313 and S315 from the COOH-terminal PEST domain of IκBβ is critical for binding to Cn. Mutations at S313/S315 of IκBβ abolished Cn binding, inhibited Cn-mediated increase of Rel proteins in the nucleus, and had a dominant-negative effect on the mitochondrial stress–induced expression of RyR1 and cathepsin L genes. Our results show the distinctive nature of mitochondrial stress–induced NFκB/Rel activation, which is independent of IKKα and IKKβ kinases and affects gene target(s) that are different from cytokine and TNFα-induced stress signaling. The results provide new insights into the role of Cn as a critical link between Ca(2+) signaling and NFκB/Rel activation.