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Review
. 2011 Jan;21(1):71-85.
doi: 10.1038/cr.2010.177. Epub 2010 Dec 21.

Non-canonical NF-κB signaling pathway

Shao-Cong Sun  1
Affiliations
Review

Non-canonical NF-κB signaling pathway

Shao-Cong Sun. Cell Res. 2011 Jan.

Abstract

The non-canonical NF-κB pathway is an important arm of NF-κB signaling that predominantly _targets activation of the p52/RelB NF-κB complex. This pathway depends on the inducible processing of p100, a molecule functioning as both the precursor of p52 and a RelB-specific inhibitor. A central signaling component of the non-canonical pathway is NF-κB-inducing kinase (NIK), which integrates signals from a subset of TNF receptor family members and activates a downstream kinase, IκB kinase-α (IKKα), for triggering p100 phosphorylation and processing. A unique mechanism of NIK regulation is through its fate control: the basal level of NIK is kept low by a TRAF-cIAP destruction complex and signal-induced non-canonical NF-κB signaling involves NIK stabilization. Tight control of the fate of NIK is important, since deregulated NIK accumulation is associated with lymphoid malignancies.

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Figures

Figure 1
Figure 1
Canonical and non-canonical NF-κB signaling pathways. Canonical pathway is triggered by numerous signals, including those mediated by innate and adaptive immune receptors. It involves activation of IKK complex by Tak1, IKK-mediated IκBα phosphorylation, and subsequent degradation, resulting in rapid and transient nuclear translocation of the prototypical NF-κB heterodimer RelA/p50. Non-canonical NF-κB pathway relies on phosphorylation-induced p100 processing, which is triggered by signaling from a subset of TNFR members. This pathway is dependent on NIK and IKKα, but not on the trimeric IKK complex, and mediates the persistent activation of RelB/p52 complex.
Figure 2
Figure 2
Positive and negative domains regulating p100 processing. The tight control of p100 processing requires its DD as well as ARD, which serve as negative regulatory domains. The NRD, responsible for p100 inducible processing, contains a phospho-degron that is phosphorylated by IKKα and bound by βTrCP of the SCFβTrCP ubiquitin ligase complex.
Figure 3
Figure 3
NIK stabilization as a mechanism of non-canonical NF-κB signaling. (A) Under normal conditions, NIK is bound by TRAF3 and recruited to the cIAP1/2 ubiquitin ligase via TRAF3 dimerization with TRAF2. The T3-T2-cIAP E3 complex mediates constant ubiquitination and proteasomal degradation of NIK, thus preventing non-canonical NF-κB activation. (B) In response to receptor crosslinking, TRAFs and cIAP1/2 are recruited to the receptor, where cIAP1/2 ubiquitinates TRAF2 and TRAF3 and stimulates their degradation. ZFP91 mediates K63 ubiquitination of NIK, which may promote stability and catalytic activity of NIK. (C) Accumulated NIK activates IKKα, which in turn phosphorylates p100, leading to p100 processing. IKKα also phosphorylates NIK to promote NIK degradation, a feedback mechanism that may control the magnitude of NIK activation.
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