Negative Feedback in Noncanonical NF-κB Signaling Modulates NIK Stability Through IKKα-Mediated Phosphorylation

Canonical and noncanonical nuclear factor kappa B (NF-kappa B) signaling are the two basic pathways responsible for the release of NF-kB 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 beta receptor (LT beta R). 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.