文摘
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Summary
The I¦ÊB 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-¦ÊB, 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-¦ÊB activation suppresses TNF¦Á-induced apoptosis. TNF¦Á-treated Ikk¦Â?/? 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¦Á-induced apoptosis in cultured cells and increasing mortality in animals. Our results reveal that IKK inhibits TNF¦Á-induced apoptosis through two distinct but cooperative mechanisms: activation of the survival factor NF-¦ÊB and inactivation of the proapoptotic BH3-only BAD protein.