Gadd45β mediates the NF-κB suppression of JNK signalling by targeting MKK7/JNKK2

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Abstract
NF-κB/Rel transcription factors control apoptosis, also known as programmed cell death. This control is crucial for oncogenesis, cancer chemo-resistance and for antagonizing tumour necrosis factor α (TNFα)-induced killing1,2. With regard to TNFα, the anti-apoptotic activity of NF-κB involves suppression of the c-Jun N-terminal kinase (JNK) cascade3,4,5. Using an unbiased screen, we have previously identified Gadd45β/Myd118, a member of the Gadd45 family of inducible factors6, as a pivotal mediator of this suppressive activity of NF-κB3. However, the mechanisms by which Gadd45β inhibits JNK signalling are not understood. Here, we identify MKK7/JNKK2 — a specific and essential activator of JNK7,8 — as a target of Gadd45β, and in fact, of NF-κB itself. Gadd45β binds to MKK7 directly and blocks its catalytic activity, thereby providing a molecular link between the NF-κB and JNK pathways. Importantly, Gadd45β is required to antagonize TNFα-induced cytotoxicity, and peptides disrupting the Gadd45β/MKK7 interaction hinder the ability of Gadd45β, as well as of NF-κB, to suppress this cytotoxicity. These findings establish a basis for the NF-κB control of JNK activation and identify MKK7 as a potential target for anti-inflammatory and anti-cancer therapy.