A Distinctive Physiological Role for IκBβ in the Propagation of Mitochondrial Respiratory Stress Signaling*

The NFκBs regulate an array of physiological and pathological processes, including propagation of mitochondrial respiratory stress signaling in mammalian cells. We showed previously that mitochondrial stress activates NFκB using a novel calcineurin-requiring pathway that is different from canonical or non-canonical pathways. This study shows that IκBβ is essential for the propagation of mitochondrial stress signaling. Knock down of IκBβ, but not IκBα, mRNA reduced the mitochondrial stress-mediated activation and nuclear translocation of cRel:p50, inhibiting expression of nuclear target genes RyR1 and cathepsin L. IκBβ mRNA knock down also reduced resistance to staurosporine-induced apoptosis and decreased in vitro invasiveness. Induced receptor switching to insulin-like growth factor-1 receptor and increased glucose uptake are hallmarks of mitochondrial stress. IκBβ mRNA knock down selectively abrogated the receptor switch and altered tubulin cytoskeletal organization. These results show that mitochondrial stress signaling uses an IκBβ-initiated NFκB pathway that is distinct from the other known NFκB pathways. Furthermore, our results demonstrate the distinctive physiological roles of the two inhibitory proteins IκBβ and IκBα