RT Journal Article
SR Electronic
T1 Negative Feedback in Noncanonical NF-κB Signaling Modulates NIK Stability Through IKKα-Mediated Phosphorylation
JF Science Signaling
JO Sci. Signal.
FD American Association for the Advancement of Science
SP ra41
OP ra41
DO 10.1126/scisignal.2000778
VO 3
IS 123
A1 Razani, Bahram
A1 Zarnegar, Brian
A1 Ytterberg, A. Jimmy
A1 Shiba, Travis
A1 Dempsey, Paul W.
A1 Ware, Carl F.
A1 Loo, Joseph A.
A1 Cheng, Genhong
YR 2010
UL http://stke.sciencemag.org/content/3/123/ra41.abstract
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.