CIKS, a connection to I kappa B kinase and stress-activated protein kinase

Pathogens, inflammatory signals, and stress cause acute transcriptional res ponses in cells. The induced expression of genes in response to these signa ls invariably involves transcription factors of the NF-kappa B and AP-1/ATF families, Activation of NF-kappa B factors is thought to be mediated prima rily via I kappa B kinases (IKK), whereas that of AP-1/ATF can be mediated by stress-activated protein kinases (SAPKs; also named Jun kinases or JNKs) . IKK alpha and IKK beta are two catalytic subunits of a core IKK complex t hat also contains the regulatory subunit NEMO (NF-kappa B essential modulat or)/IKK gamma. The latter protein is essential for activation of the IKKs. but its mechanism of action is not known. Here we describe the molecular cl oning of CIKS (connection to IKK and SAPK/JNK), a previously unknown protei n that directly interacts with NEMO/IKK gamma in cells. When ectopically ex pressed, CIKS stimulates IKK and SAPK/JNK kinases and it transactivates an NF-kappa B-dependent reporter. Activation of NF-kappa B is prevented in the presence of kinase-deficient. interfering mutants of the IKKs. CIKS may he lp to connect upstream signaling events to IKK and SAPK/JNK modules. CIKS c ould coordinate the activation of two stress-induced signaling pathways. fu nctions reminiscent of those noted for tumor necrosis factor receptor-assoc iated factor adaptor proteins.