Controlling the fate of NIK: a central stage in noncanonical NF-kappaB signaling

Abstract

The noncanonical nuclear factor kappaB (NF-kappaB) pathway is a specific arm of NF-kappaB signaling that regulates important aspects of immune function. Activation of this pathway centers on the modulation of a pivotal signaling component: NF-kappaB-inducing kinase (NIK). Under normal conditions, NIK undergoes constitutive degradation, which keeps its abundance below the threshold required for its function, and signal-induced activation of the noncanonical NF-kappaB pathway is coupled with the stabilization and accumulation of NIK. A study now shows that signal-induced accumulation of NIK is subject to feedback control, which involves its phosphorylation by a downstream kinase, inhibitor of kappaB (IkappaB) kinase alpha (IKKalpha), and degradation. Thus, controlling the fate of NIK is emerging as a central mechanism in noncanonical NF-kappaB signaling.

Fig. 1

Basal and feedback mechanisms that regulate NIK activity. (A) Under unstimulated conditions, NIK is constantly targeted for ubiquitination and degradation by the redundant functions of the E3 ubiquitin ligases cIAP1 and cIAP2, which do not directly interact with NIK but are recruited to NIK through TRAF2 and TRAF3, which interact with cIAP1/2 and NIK, respectively. The basal degradation of NIK may keep its abundance below a threshold required for function, thus preventing signal-independent activation of the processing of p100. (B) In response to receptor-dependent signals, TRAF2 or TRAF3, or both, are recruited to the signaling receptor and are targeted for degradation by cIAP-mediated ubiquitination, which triggers the release and stabilization of NIK. NIK accumulates and activates IKKα, which triggers the processing of p100. Activated IKKα also phosphorylates NIK and induces its degradation, which prevents an overaccumulation of NIK in activated cells. The IKKα-mediated feedback mechanism controls the magnitude of the accumulation of NIK but may not be able to completely shut off noncanonical NF-κB signaling.