Science Signaling  29 Jan 2013:
Vol. 6, Issue 260, pp. ec31
DOI: 10.1126/scisignal.2004004

The cytokine tumor necrosis factor–α (TNF-α) induces apoptosis through its activation of caspase and c-Jun N-terminal kinase (JNK) signaling pathways. Protection from TNF-α–induced apoptosis is thought to be provided mostly by nuclear factor κB (NF-κB) signaling, which results in the expression of gene products that inhibit caspase and JNK signaling. Central to the activation of NF-κB in this pathway is the inhibitor of κB (IκB) kinase (IKK) complex, which phosphorylates IκB, targeting it for proteasomal destruction and liberating NF-κB dimers to translocate to the nucleus to activate target gene expression. Yan et al. provide evidence of an alternative pathway by which the IKK complex inhibits TNF-α–induced apoptosis independently of NF-κB signaling. Treatment with TNF-α resulted in more rapid apoptosis in mouse embryonic fibroblasts (MEFs) deficient in the gene encoding the IKK component IKKβ than in MEFs deficient in the NF-κB subunits RelA and cRel. Knockdown of the proapoptotic protein BAD reduced TNF-α–induced apoptosis in IKKβ-deficient MEFs but not in RelA- and cRel-deficient MEFs. Western blotting analysis showed that TNF-α induced the phosphorylation of BAD in wild-type MEFs but not in IKKβ-deficient MEFs, and in vitro kinase assays showed that IKK phosphorylated BAD at Ser26. MEFs expressing the S26A mutant BAD protein were more susceptible to TNF-α–induced apoptosis than were MEFs expressing wild-type BAD. Phosphorylation of BAD at Ser26 prevented its translocation to the mitochondria and its interaction with (and inactivation of) the antiapoptotic protein BCL-XL. BAD-deficient mice reconstituted with BAD S26A by adenoviral infection showed enhanced mortality in response to TNF-α compared with that of BAD-deficient mice reconstituted with wild-type BAD. Together, these data suggest a mechanism by which IKK inhibits TNF-α–induced apoptosis independently of NF-κB.

J. Yan, J. Xiang, Y. Lin, J. Ma, J. Zhang, H. Zhang, J. Sun, N. N. Danial, J. Liu, A. Lin, Inactivation of BAD by IKK inhibits TNFα-induced apoptosis independently of NF-κB activation. Cell 152, 304–315 (2013). [PubMed]