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.