PT  - JOURNAL ARTICLE
AU  - Razani, Bahram
AU  - Zarnegar, Brian
AU  - Ytterberg, A. Jimmy
AU  - Shiba, Travis
AU  - Dempsey, Paul W.
AU  - Ware, Carl F.
AU  - Loo, Joseph A.
AU  - Cheng, Genhong
TI  - Negative Feedback in Noncanonical NF-κB Signaling Modulates NIK Stability Through IKKα-Mediated Phosphorylation
AID  - 10.1126/scisignal.2000778
DP  - 2010 May 25
TA  - Science Signaling
PG  - ra41--ra41
VI  - 3
IP  - 123
4099  - http://stke.sciencemag.org/content/3/123/ra41.short
4100  - http://stke.sciencemag.org/content/3/123/ra41.full
SO  - Sci. Signal.2010 May 25; 3
AB  - Canonical and noncanonical nuclear factor κB (NF-κB) signaling are the two basic pathways responsible for the release of NF-κB dimers from their inhibitors. Enhanced NF-κB signaling leads to inflammatory and proliferative diseases; thus, inhibitory pathways that limit its activity are critical. Whereas multiple negative feedback mechanisms control canonical NF-κB signaling, none has been identified for the noncanonical pathway. Here, we describe a mechanism of negative feedback control of noncanonical NF-κB signaling that attenuated the stabilization of NF-κB–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 κB (IκB) kinase α (IKKα) was previously thought to lie downstream of NIK in the noncanonical NF-κB pathway; we showed that phosphorylation of NIK by IKKα destabilized NIK. In the absence of IKKα-mediated negative feedback, the abundance of NIK increased after receptor ligation. A form of NIK with mutations in the IKKα-targeted serine residues was more stable than wild-type NIK and resulted in increased noncanonical NF-κB 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, IKKα-dependent destabilization of NIK prevents the uncontrolled activity of the noncanonical NF-κB pathway after receptor ligation.