A single NFκB system for both canonical and non-canonical signaling - PubMed (original) (raw)

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A single NFκB system for both canonical and non-canonical signaling

Vincent Feng-Sheng Shih et al. Cell Res. 2011 Jan.

Abstract

Two distinct nuclear factor κB (NFκB) signaling pathways have been described; the canonical pathway that mediates inflammatory responses, and the non-canonical pathway that is involved in immune cell differentiation and maturation and secondary lymphoid organogenesis. The former is dependent on the IκB kinase adaptor molecule NEMO, the latter is independent of it. Here, we review the molecular mechanisms of regulation in each signaling axis and attempt to relate the apparent regulatory logic to the physiological function. Further, we review the recent evidence for extensive cross-regulation between these two signaling axes and summarize them in a wiring diagram. These observations suggest that NEMO-dependent and -independent signaling should be viewed within the context of a single NFκB signaling system, which mediates signaling from both inflammatory and organogenic stimuli in an integrated manner. As in other regulatory biological systems, a systems approach including mathematical models that include quantitative and kinetic information will be necessary to characterize the network properties that mediate physiological function, and that may break down to cause or contribute to pathology.

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Figures

Figure 1

Figure 1

Components of the IKK-IκB-NFκB signaling system. The IKK form canonical NEMO-containing (green) complexes and non-canonical (blue) complexes, which control the degradation of IκB proteins and precursor processing. IκBα, IκBβ, IκBɛ and the IκB activities within the IκBsome IκBγ and IκBδ are able to sequester NFκB dimers. The p50 and p52 NFκB proteins are generated from the processing of newly synthesized precursor proteins p105 and p100, respectively. The five NFκB family members (RelA/p65, cRel, RelB, p52 and p50) can potentially form 15 heterodimers and homodimers that can bind to a large number of κB sites in DNA, which are characterized by a remarkably broad sequence consensus.

Figure 2

Figure 2

The NFκB signaling module consisting of canonical and non-canonical pathways. The non-canonical pathway is activated through developmental signals activating NIK/IKK1. This activation results in the degradation of IκBδ and processing of p100 and allows the nuclear translocation of RelA:p50, RelB:p50 and RelB:p52 dimers, which activate genes responsible for organ development. The canonical pathway is activated through pathogen and inflammatory signals activating NEMO/IKK. This activation results in the degradation of IκBα/IκBβ/IκBɛ, allowing for the nuclear translocation of RelA:p50, RelA:RelA and cRel:p50 dimers, which then activate genes responsible for inflammation and survival.

Figure 3

Figure 3

Mechanisms of canonical IKK activation. Several distinct pathways of canonical IKK activation have been described: LEFT, upon TNFR engagement, receptor-associated proteins such as TRADD and TRAF2/5 recruit the E2/E3 ligase complex consisting of cIAP1 and UbcH5. cIAP1/UbcH5 subsequently conjugate ubiquitin chains of various types of linkages to RIP1, which allows for TAK1 complex and IKK binding. The binding of Ub by the TAK1 complex activates TAK1 and allows it to activate IKK; in addition, Ub binding by the IKK complex induces IKK activation, allowing IKK to _trans_-autophosphorylate. Center, upon ligand binding of the TNFR, the ubiquitin ligase complex consisting of HOIP and HOIL-1L, known as LUBAC, is recruited by TRADD, TRAF2 and cIAP1. LUBAC conjugates linear-linked ubiquitin to NEMO in the IKK complex, resulting in IKK activation via _trans_-autophosphorylation. Right, when members of the TLR/IL-1R family are engaged, receptor-associated proteins Myd88 and IRAK recruit the E2/E3 ligase complex consisting of TRAF6 and Ubc13, which conjugates K63-linked ubiquitin chains to IRAK1. The TAK1 complex binds these K63 Ub chains, leading to TAK1 activation, presumably by _trans_-autophosphorylation. TAK1 subsequently activates nearby IKK. How these and possibly other mechanisms that result in canonical IKK activation combine to transduce signaling from different receptors remains an active area of investigation.

Figure 4

Figure 4

The canonical IKK-NFκB pathway. Upon canonical IKK activation, the classical IκBs, IκBα, -β, -ɛ, which sequester NFκB to the cytoplasm in a stoichiometric manner, are phosphorylated on specific N-terminal residues that function as docking sites for the E3 ubiquitin ligase complex SCF/βTRCP. Ubiquitinated IκBα is degraded by the 26S proteasome, allowing for translocation of NFκB into the nucleus. Nuclear NFκB activity induces the expression of IκBα and IκBɛ, providing for negative feedback. Free IκB proteins are rapidly degraded in a ubiquitin-independent manner by the 20S proteasome, presumably in conjunction with alternate proteasome targeting or activating proteins.

Figure 5

Figure 5

Mechanisms of canonical pathway attenuation. The best characterized attenuation mechanism is negative feedback synthesis of IκB proteins (1). IκBα was recently shown to have the ability to enhance the dissociation rate of NFκB from DNA, which may facilitate its negative feedback control function (2). In addition, DNA-bound RelA NFκB, when phosphorylated on S536 by nuclear IKK complexes, was shown to be subjected to ubiquitination by the E3 ligase PIAS1, which targets NFκB to degradation (3). The ubiquitin protease A20, a highly inducible NFκB target gene, attenuates the IKK activation pathway by counteracting E3 ligases involved in the formation of ubiquitin chains that are critical signaling scaffolds (4). In addition, canonical IKK was proposed to undergo autophosphorylation that results in an inactivated kinase (5); a recycling step is necessary to return IKK back to the activatable state.

Figure 6

Figure 6

The non-canonical NFκB pathway. Receptor engagement leads to recruitment and activation of cIAP1/2 mediated by TRAF2 resulting in the degradation of TRAF3. Decreased levels of TRAF3 stabilize NIK, which in turn activates IKK1 activity. Degradation of IκBδ following non-canonical IKK activation releases RelA:p50 or RelB:p50 dimers sequestered by IκBδ. Processing of newly synthesized p100 also occurs and generates RelB:p52 complex, whose levels slowly build up to provide sustained activity of the RelB:p52 dimer. Translocation of NFκB dimers to the nucleus activates gene expression program.

Figure 7

Figure 7

Wiring diagrams of the NFκB signaling system to chart crosstalk between canonical and non-canonical signaling pathways. (A) Non-canonical control of RelA:p50. RelA:p50 is inhibited by not only IκBα, -β, -ɛ, but also IκBδ. Whereas inflammatory canonical signals lead to degradation of IκBα, -β, -ɛ, developmental signals engage the non-canonical pathway to disrupt IκBδ activity; however, both result in the nuclear translocation of RelA:p50. Interestingly, prior canonical signaling history results in an enhancement of the non-canonical-RelA:p50 axis, due to inducible expression of p100. (B) Canonical control of RelB:p52 activation. Expression of p100 and RelB are dependent on RelA:p50 activity and therefore canonical signals. The amount of basal RelB expression, controlled by constitutive canonical pathway activity, rather than the inducible p100 expression, is the main determinant of the strength of non-canonical signaling.

Figure 8

Figure 8

Wiring diagrams of the NFκB signaling system to chart the interdependence and functional overlap of nfκb1 and nfκb2 gene products. (A) The NFκB signaling system in nfκb2−/− cells. Without its normal binding partner p52, RelB will bind p50 to form RelB:p50 dimers, which accumulate in the nucleus. As a result, constitutive RelB:p50 activity compensates for the loss of inducible RelB:p52 activity. (B) The NFκB signaling system in nfκb1−/− cells. Without its normal binding partner p50, RelA will bind p52 causing an increase in constitutive p100 processing and thus a depletion of the IκBδ and p100 pool, which is required for RelB:p52 activation. Though the canonical pathway is largely preserved in _nfκb1_−/− cells, compensation by p52 weakens the non-canonical pathway.

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