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Review
. 2010 Feb;2(2):a000166.
doi: 10.1101/cshperspect.a000166.

Ubiquitination and degradation of the inhibitors of NF-kappaB

Naama Kanarek  1 , Nir London, Ora Schueler-Furman, Yinon Ben-Neriah
Affiliations
Review

Ubiquitination and degradation of the inhibitors of NF-kappaB

Naama Kanarek et al. Cold Spring Harb Perspect Biol. 2010 Feb.

Abstract

The key step in NF-kappaB activation is the release of the NF-kappaB dimers from their inhibitory proteins, achieved via proteolysis of the IkappaBs. This irreversible signaling step constitutes a commitment to transcriptional activation. The signal is eventually terminated through nuclear expulsion of NF-kappaB, the outcome of a negative feedback loop based on IkappaBalpha transcription, synthesis, and IkappaBalpha-dependent nuclear export of NF-kappaB (Karin and Ben-Neriah 2000). Here, we review the process of signal-induced IkappaB ubiquitination and degradation by comparing the degradation of several IkappaBs and discussing the characteristics of IkappaBs' ubiquitin machinery.

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Figures

Figure 1.
Figure 1.
Accommodation of peptide degrons of different lengths into the β-TrCP binding groove. The β-TrCP WD40 domain is shown in white surface representation from a top view (1P22:A); the two phosphorylated Serine residues that are conserved among all the peptides are shown in stick representation; and different peptide backbones are colored according to the peptide: The β-catenin peptide is shown in red (1P22:C); a model of the IκBα peptide (DSGLDS) is shown in blue; p105 peptide (DSGVETS) in yellow; and CDC25B peptide (DSGFCLDS) in green. Note that with increasing length of the spacer between the two phosphorylated serine residues, the hydrophobic part of the peptide binds deeper into the pocket.
Figure 2.
Figure 2.
Ubiquitin-mediated proteolysis at the central stage of the NF-κB. Many regulatory steps in the NF-κB pathway involve ubiquitin-regulated proteolysis. In resting cells (right panel), basal level processing of the NF-κB1 precursor p105 to p50, mediated by a yet unidentified E3(s) (E3x), is the major proteolytic event. The processing product p50 associates with p65 to generate the NF-κB heterodimer, maintained inactive in the cytosol through association with an inhibitor: one of the “professional IκBs” or an NF-κB precursor (both p105 and p100). On cell stimulation (left panel), TNFα and LTα/β signal-mediated degradation of the IκBs and processing NF-κB2 (p100) to the mature p52 subunit, respectively, are the key proteolytic steps. All these ubiquitin-proteolysis events are controlled by a single E3 ubiquitin ligase, β-TrCP. A prerequisite for β-TrCP-induced ubiquitination is phosphorylation of its target proteins, mediated by IKK (not shown). Following IκB degradation, NF-κB accumulates in the nucleus and is free to induce transcriptional activation. Another major feature of the NF-κB pathways is the negative feedback control (red lines) by which first the newly transcribed IκBα and then the NF-κB precursors function to shorten signal duration by inhibiting NF-κB-controlled transcription. Pairing IκBα transcription and resynthesis to its rapid degradation shapes an oscillatory NF-κB response, which might have a particular regulatory significance, yet to be discovered. IκBε transcription by NF-κB function to reduce the oscillatory magnitude of the response and stabilize it during longer stimulations.
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