Inactivation of BAD by IKK Inhibits TNF¦Á-Induced Apoptosis Independently of NF-¦ÊB Activation

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• 作者：Jie Yan¹ ; Jialing Xiang² ; Yutin Lin² ; Jingui Ma¹ ; Jiyan Zhang¹ ; ³ ; Hao Zhang⁴ ; Jisheng Sun⁴ ; Nika N. Danial⁵ ; Jing Liu⁶ ; Anning Lin¹ ; ⁴ ; ^{anninglin@bsd.uchicago.edu}
• 刊名：Cell
• 出版年：2013
• 出版时间：17 January, 2013
• 年：2013
• 卷：152
• 期：1-2
• 页码：304-315
• 全文大小：1619 K

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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.