Journal
CELL
Volume 152, Issue 1-2, Pages 304-315Publisher
CELL PRESS
DOI: 10.1016/j.cell.2012.12.021
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Funding
- National Basic Research Program of China [2012CB910801]
- National Natural Science Foundation of China [31130035]
- Chinese Academy of Sciences [SIBS2010CSP001]
- National Institutes of Health [CA100460, CA128114, GM081603]
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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.
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