Inactivation of BAD by IKK inhibits TNFα-induced apoptosis independently of NF-κB activation

Cell. 2013 Jan 17;152(1-2):304-15. doi: 10.1016/j.cell.2012.12.021.

Abstract

The IκB 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-κB, 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-κB activation suppresses TNFα-induced apoptosis. TNFα-treated Ikkβ(-/-) 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 TNFα-induced apoptosis in cultured cells and increasing mortality in animals. Our results reveal that IKK inhibits TNFα-induced apoptosis through two distinct but cooperative mechanisms: activation of the survival factor NF-κB and inactivation of the proapoptotic BH3-only BAD protein.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Fibroblasts / cytology
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism*
  • Mice
  • Mice, Knockout
  • NF-kappa B / metabolism*
  • Phosphorylation
  • Serine / metabolism
  • Tumor Necrosis Factor-alpha / metabolism*
  • bcl-Associated Death Protein / chemistry
  • bcl-Associated Death Protein / genetics
  • bcl-Associated Death Protein / metabolism*
  • bcl-X Protein / metabolism

Substances

  • Bad protein, mouse
  • Bcl2l1 protein, mouse
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • bcl-Associated Death Protein
  • bcl-X Protein
  • Serine
  • I-kappa B Kinase