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PNAS 97 (19): 10494-10499

Copyright © 2000 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / GENETICS

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

Antonio Leonardi{dagger},{ddagger}, Alain Chariot{dagger}, Estefania Claudio, Kirk Cunningham, and Ulrich Siebenlist§

Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1876

Received for publication May 25, 2000.

Abstract: Pathogens, inflammatory signals, and stress cause acute transcriptional responses in cells. The induced expression of genes in response to these signals 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 primarily 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). IKKα and IKKβ are two catalytic subunits of a core IKK complex that also contains the regulatory subunit NEMO (NF-{kappa}B essential modulator)/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 cloning of CIKS (connection to IKK and SAPK/JNK), a previously unknown protein that directly interacts with NEMO/IKK{gamma} in cells. When ectopically expressed, 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 help to connect upstream signaling events to IKK and SAPK/JNK modules. CIKS could coordinate the activation of two stress-induced signaling pathways, functions reminiscent of those noted for tumor necrosis factor receptor-associated factor adaptor proteins.

{dagger} A.L. and A.C. contributed equally to this work.

{ddagger} Present address: Dipartimento di Biologia e Patologia Cellulare e Molecolare, Federico II University of Naples, Via Pansini 5, 80131 Naples, Italy.

§ To whom reprint requests should be addressed. E-mail: US3N{at}nih.gov.

Edited by David V. Goeddel, Tularik, Inc., South San Francisco, CA, and approved July 21, 2000

This paper was submitted directly (Track II) to the PNAS office.

Data deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. AF272151).

Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.190245697.

Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.190245697

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