Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2013:42:443-68.
doi: 10.1146/annurev-biophys-083012-130338. Epub 2013 Mar 11.

Molecular basis of NF-κB signaling

Johanna Napetschnig  1 , Hao Wu
Affiliations
Review

Molecular basis of NF-κB signaling

Johanna Napetschnig et al. Annu Rev Biophys. 2013.

Abstract

NF-κB (nuclear factor kappa B) family transcription factors are master regulators of immune and inflammatory processes in response to both injury and infection. In the latent state, NF-κBs are sequestered in the cytosol by their inhibitor IκB (inhibitor of NF-κB) proteins. Upon stimulations of innate immune receptors such as Toll-like receptors and cytokine receptors such as those in the TNF (tumor necrosis factor) receptor superfamily, a series of membrane proximal events lead to the activation of the IKK (IκB kinase). Phosphorylation of IκBs results in their proteasomal degradation and the release of NF-κB for nuclear translocation and activation of gene transcription. Here, we review the plethora of structural studies in these NF-κB activation pathways, including the TRAF (TNF receptor-associated factor) proteins, IKK, NF-κB, ubiquitin ligases, and deubiquitinating enzymes. Although these structures only provide snapshots of isolated processes, an emerging picture is that these signaling cascades coalesce into large oligomeric signaling complexes, or signalosomes, for signal propagation.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Simplified view of the TLR/IL-1R (left) and TNFR (right) pathways leading to activation of NF-κB. Known interactions between proteins are indicated and discussed in detail in the text. Abbreviations: IL-1R, interleukin-1 receptor; NF-κB, nuclear factor κB; TLR, Toll-like receptor; TNFR, tumor necrosis factor receptor.
Figure 2
Figure 2
Structures of NF-κB and IκBs. (a) Domain organizations of representative members. (b) Space-filling model of the crystal structure of the p50/p65 heterocomplex bound to DNA. (c) The same structure shown in ribbon diagrams in two orientations. (d) Space-filling model of the crystal structure of p50/p65 heterocomplex bound to IκBα. NLS of p65 is shown in red. (e) The same structure shown in ribbon diagrams in two orientations. (f) Superposition of p65 in the IκBα-bound form (blue) and DNA-bound form (orange). Abbreviations: CTD, C-terminal domain; IκB, inhibitor of NF-κB; NF-κB, nuclear factor κB; NLS, nuclear localization signal; NTD, N-terminal domain.
Figure 3
Figure 3
Structural overview of (a) Lys48-linked, (b) Lys63-linked, and (c) linear di-ubiquitin (di-Ub) showing the resulting different overall conformation. Lys48, Lys63, and Met1 are highlighted in red. Note that in linear di-Ub chains, no lysine residue is used for the linker.
Figure 4
Figure 4
Structures of the IKK complex. (a) Domain organizations. (b) Crystal structure of IKKβ dimer. (c) Crystal structure of IKKβ NBD in complex with the N-terminal kinase-binding domain (HLX1) of NEMO. (d) Crystal structure of NEMO HLX2 in complex with vFLIP. (e) Crystal structure of CC2-LZ of NEMO in complex with linear di-Ub. (f) Structure of the NEMO ZF domain. (g) A model of full-length NEMO dimer. Abbreviations: di-Ub, di-ubiquitin; IKK, IκB kinase; NBD, NEMO-binding domain; NEMO, NF-κB essential modulator; ZF, zinc finger.
Figure 5
Figure 5
Structures of TRAFs. (a) Domain organizations. (b) Crystal structure of the dimeric RING and ZF domains (ZF1-3) of TRAF6. (c) Crystal structure of the dimeric RING and ZF domain (ZF1) of TRAF2. (d) Crystal structure of TRAF6 RING and ZF domain (ZF1) in complex with Ubc13. (e) Crystal structure of TRAF2 CC in complex with cIAP2 BIR1 domain. (f, g) Crystal structure of the TRAF domain of TRAF2 in complex with a peptide from the CD40 receptor in space-filling and ribbon diagrams, respectively. (h, i) Crystal structure of the TRAF domain of TRAF2 in complex with the NTD of TRADD in space-filling and ribbon diagrams, respectively. (j) An infinite aggregation model of full-length TRAF proteins by alternating dimerization and trimerization. Abbreviations: CC, coiled coil; NTD, N-terminal domain; TRAF, tumor necrosis factor (TNF) receptor–associated factor.
Figure 6
Figure 6
Structures of the Myddosome and other membrane-proximal interactions in the TLR/IL-1R pathway. (a) Domain organizations. (b) Crystal structure of the DD complex of the Myddosome in two orientations, showing a structure with 6 MyD88, 4 IRAK4, and 4 IRAK1 or IRAK2 molecules. (c) A structural model of the membrane-proximal events in TLR signaling. Abbreviations: DD, death domain; IL-1R, interleukin-1 receptor; IRAK, interleukin-1 receptor (IL-1R)-associated kinase; MyD88, myeloid differentiation primary-response gene 88; TLR, Toll-like receptor.
Figure 7
Figure 7
The TAK1 complex and deubiquitinases in downregulating NF-κB signaling. (a) Domain organizations of TAK1 complex components. (b) Crystal structure of TAK1 kinase domain in complex with an activating peptide from TAB1. (c) Crystal structure of TAB2 NZF in complex with Lys63-linked di-ubiquitin. (d) Domain organizations of deubiquitinases A20 and CYLD. (e) Crystal structure of the OTU domain of A20. (f) Crystal structure of the fourth ZF domain of A20 in complex with three ubiquitin molecules. (g) Crystal structure of the USP domain of CYLD. The B-box is a small zinc-binding domain similar to RING domains. Abbreviations: NZF, Npl4 zinc finger; OTU, ovarian tumor domain; USP, ubiquitin-specific protease; ZF, zinc finger.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Baeuerle PA, Baltimore D. I kappa B: a specific inhibitor of the NF-kappa B transcription factor. Science. 1988;242(4878):540–46. - PubMed
    1. Bagnéris C, Ageichik AV, Cronin N, Wallace B, Collins M, et al. Crystal structure of a vFlip-IKKγ complex: insights into viral activation of the IKK signalosome. Mol Cell. 2008;30(5):620–31. - PubMed
    1. Banner DW, D’Arcy A, Janes W, Gentz R, Schoenfeld HJ, et al. Crystal structure of the soluble human 55 kd TNF receptor–human TNFβ complex: implications for TNF receptor activation. Cell. 1993;73(3):431–45. - PubMed
    1. Bassères DS, Baldwin AS. Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression. Oncogene. 2006;25(51):6817–30. - PubMed
    1. Bianchi K, Meier P. A tangled web of ubiquitin chains: breaking news in TNF-R1 signaling. Mol Cell. 2009;36(5):736–42. - PubMed

Publication types

-