Inactivation of BAD by IKK Inhibits TNFα-Induced Apoptosis Independently of NF-κB Activation

The I kappa B kinase complex (IKK) is a key regulator of immune responses, inflammation, cell survival, and tumorigenesis. The prosurvival function of IKK centers on activation of the transcription factor NF-kappa B, whose target gene products inhibit caspases and prevent prolonged JNK activation. Here, we report that inactivation of the BH3-only protein BAD by IKK independently of NF-kappa B activation suppresses TNF alpha-induced apoptosis. TNF alpha-treated Ikk beta(-/-) mouse embryonic fibroblasts (MEFs) undergo apoptosis significantly faster than MEFs deficient in both RelA and cRel due to lack of inhibition of BAD by IKK. IKK phosphorylates BAD at serine-26 (Ser26) and primes it for inactivation. Elimination of Ser26 phosphorylation promotes BAD proapoptotic activity, thereby accelerating TNF alpha-induced apoptosis in cultured cells and increasing mortality in animals. Our results reveal that IKK inhibits TNF alpha-induced apoptosis through two distinct but cooperative mechanisms: activation of the survival facto r NF-kappa B and inactivation of the proapoptotic BH3-only BAD protein.