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Sci. Signal., 25 May 2010
Vol. 3, Issue 123, p. ra41
[DOI: 10.1126/scisignal.2000778]


Negative Feedback in Noncanonical NF-{kappa}B Signaling Modulates NIK Stability Through IKK{alpha}-Mediated Phosphorylation

Bahram Razani1,2, Brian Zarnegar1, A. Jimmy Ytterberg3*, Travis Shiba1, Paul W. Dempsey1, Carl F. Ware4,5, Joseph A. Loo3,6, and Genhong Cheng1{dagger}

1 Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, 609 Charles E. Young Drive East, Los Angeles, CA 90095, USA.
2 Medical Scientist Training Program, David Geffen School of Medicine at the University of California Los Angeles, 23-385 Center for the Health Sciences, Box 957041/MC 704117, Los Angeles, CA 90095, USA.
3 Department of Chemistry and Biochemistry, University of California Los Angeles, 607 Charles E. Young Drive East, Los Angeles, CA 90095, USA.
4 Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
5 Department of Biology, University of California San Diego, San Diego, CA 92093, USA.
6 Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.

* Present address: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.

Abstract: Canonical and noncanonical nuclear factor {kappa}B (NF-{kappa}B) signaling are the two basic pathways responsible for the release of NF-{kappa}B dimers from their inhibitors. Enhanced NF-{kappa}B signaling leads to inflammatory and proliferative diseases; thus, inhibitory pathways that limit its activity are critical. Whereas multiple negative feedback mechanisms control canonical NF-{kappa}B signaling, none has been identified for the noncanonical pathway. Here, we describe a mechanism of negative feedback control of noncanonical NF-{kappa}B signaling that attenuated the stabilization of NF-{kappa}B–inducing kinase (NIK), the central regulatory kinase of the noncanonical pathway, induced by B cell–activating factor receptor (BAFF-R) and lymphotoxin β receptor (LTβR). Inhibitor of {kappa}B (I{kappa}B) kinase {alpha} (IKK{alpha}) was previously thought to lie downstream of NIK in the noncanonical NF-{kappa}B pathway; we showed that phosphorylation of NIK by IKK{alpha} destabilized NIK. In the absence of IKK{alpha}-mediated negative feedback, the abundance of NIK increased after receptor ligation. A form of NIK with mutations in the IKK{alpha}-targeted serine residues was more stable than wild-type NIK and resulted in increased noncanonical NF-{kappa}B signaling. Thus, in addition to the regulation of the basal abundance of NIK in unstimulated cells by a complex containing tumor necrosis factor receptor–associated factor (TRAF) and cellular inhibitor of apoptosis (cIAP) proteins, IKK{alpha}-dependent destabilization of NIK prevents the uncontrolled activity of the noncanonical NF-{kappa}B pathway after receptor ligation.

{dagger} To whom correspondence should be addressed. E-mail: gcheng{at}

Citation: B. Razani, B. Zarnegar, A. J. Ytterberg, T. Shiba, P. W. Dempsey, C. F. Ware, J. A. Loo, G. Cheng, Negative Feedback in Noncanonical NF-{kappa}B Signaling Modulates NIK Stability Through IKK{alpha}-Mediated Phosphorylation. Sci. Signal. 3, ra41 (2010).

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