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Signaling via the NFκB system

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The nuclear factor kappa B (NFκB) family of transcription factors is a key regulator of immune development, immune responses, inflammation, and cancer. The NFκB signaling system (defined by the interactions between NFκB dimers, IκB regulators, and IKK complexes) is responsive to a number of stimuli, and upon ligand–receptor engagement, distinct cellular outcomes, appropriate to the specific signal received, are set into motion. After almost three decades of study, many signaling mechanisms are well understood, rendering them amenable to mathematical modeling, which can reveal deeper insights about the regulatory design principles. While other reviews have focused on upstream, receptor proximal signaling (Hayden MS, Ghosh S. Signaling to NF‐κB. Genes Dev 2004, 18:2195–2224; Verstrepen L, Bekaert T, Chau TL, Tavernier J, Chariot A, Beyaert R. TLR‐4, IL‐1R and TNF‐R signaling to NF‐κB: variations on a common theme. Cell Mol Life Sci 2008, 65:2964–2978), and advances through computational modeling (Basak S, Behar M, Hoffmann A. Lessons from mathematically modeling the NF‐κB pathway. Immunol Rev 2012, 246:221–238; Williams R, Timmis J, Qwarnstrom E. Computational models of the NF‐KB signalling pathway. Computation 2014, 2:131), in this review we aim to summarize the current understanding of the NFκB signaling system itself, the molecular mechanisms, and systems properties that are key to its diverse biological functions, and we discuss remaining questions in the field. WIREs Syst Biol Med 2016, 8:227–241. doi: 10.1002/wsbm.1331

The canonical nuclear factor κ B (NFκB) activation pathway. (a) Schematic depiction of the canonical NFκB signaling pathway. Multiple inflammatory signals activate the complex containing NEMO and IKK1/2. IKK1/2 phosphorylates NFκB‐bound IκBs, targeting them for ubiquitination and proteasomal degradation. Free IκBs also undergo constitutive degradation via a ubiquitin‐independent proteasomal degradation pathway. As IκBs are degraded, free NFκB is then able to translocate to the nucleus where it binds to κB sites on DNA and activates gene expression. IκBα, β, and ε are themselves NFκB target genes, along with p100 that can form higher‐molecular‐weight complexes that inhibit NFκB. (b) Diagram of the regulatory logic of the canonical NFκB signaling network. Canonical signals activate NEMO/IKK, downregulating IκBs and reducing inhibition of NFκB. Free NFκB then translocates to the nucleus where it upregulates IκBs and p100 and in turn IκBδ.
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Signaling crosstalk between canonical and noncanonical pathways. (a) Diagram of dual roles of Nfkb2/p100 and NIK within the noncanonical pathway that together with the inducible expression of Nfkb2/p100 mediate two crosstalk functions. (1) NIK/IKK1 processes p100 into p52, enabling the activity of RelB. (2) NIK degrades IκBδ, allowing for sustained RelA activity. (b) Canonical pathway activity may boost noncanonical pathway activation of RelB:p52. Novel model simulations that illustrate how noncanonical pathway activation of RelB:p52 may be boosted by increasing constitutive canonical pathway activities. (c) A noncanonical pathway stimulus may prolong canonical pathway‐induced NFκB activity. In B cells, BAFF may potentiate late IgM‐induced cRel activity.
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Mechanisms regulating nuclear factor κ B (NFκB) dimer generation. (a) Diagram of NFκB monomer synthesis and processing. All NFκB monomers and precursors are NFκB target genes and induced, to varying extents, by NFκB. RelA/RelB/cRel polypeptides are synthesized in a complete form, ready to dimerize into functional NFκB dimers. p105 is a precursor to p50 that must be cleaved in a process thought to be dependent on IKK2. p100 must be processed via a NIK/IKK1‐dependent pathway into mature p52 before it can dimerize into NFκB. (b) Schematic of the NFκB dimerization process. Monomers must dimerize before they are transcriptionally active. The affinity of binding between monomers varies with two large, activation domain proteins having low affinity. IκBβ can act as a chaperone, enhancing the effective binding affinity of RelA to form homodimer by stabilizing this normally weak affinity dimer. (c) Table of the combinatorial composition of potential NFκB dimers, indicating their capacities to bind DNA (indicated by horizontal line) and to activate transcription (indicated by arrows). (d) Diagram of IKK’s multiple points of control over NFκB dimer formation. (1) The IKK kinases upregulates monomer expression by activating NFκB‐responsive promoters. (2) IKK1 and IKK2 activities promote processing of p100 to p52 and p105 to p50. (3) IKKs lead to the degradation of IκBs that may function as dimerization chaperones (as for example IκBβ for RelA homodimer) as well as inhibitors.
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Nuclear factor κ B (NFκB) activation by ribotoxic and genotoxic stresses. (a) Schematic depiction of alternative methods of NFκB activation. Ribotoxic stress inducers lead to the phosphorylation of initiation factor eIF2α through the action of kinases GCN2 and PERK. Once active, eIF2α inhibits translation initiation, thereby reducing synthesis of IκBs. The reduction in IκB leads to more free NFκB that localizes to the nucleus and binds DNA to promote target gene expression. Genotoxic stress inducers lead to the phosphorylation of ATM and induce complex formation with NEMO in the nucleus. NEMO is phosphorylated and exported into the cytoplasm where it associates with ELKS and stimulates IKK2‐containing complexes. Activation of NEMO/IKK2 complexes results in increased IκB degradation and localization of NFκB to the nucleus. (b) Diagram of the regulatory logic of alternative methods of NFκB activation. UV stress response through GCN2/PERK upregulates eIF2α which in turn suppresses IκBs. The reduced IκB synthesis reduces the inhibition of NFκB and increases nuclear NFκB and target gene expression. In response to DNA damage, ATM is upregulated and activates NEMO through a complex with ELKS. Increased NEMO/IKK2 activation results in suppression of IκBs.
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The noncanonical nuclear factor κ B (NFκB) activation pathway. (a) Schematic depiction of the noncanonical NFκB signaling pathway. Developmental signals activate the NIK/IKK1 complex that phosphorylates p100. Most p100 is found in a higher‐molecular‐weight inhibitory complex (IκBδ). Upon phosphorylation, p100 is processed into p52 and is then available to bind RelB, creating a dimer that localizes to the nucleus and binds DNA to activate transcription. Active NIK/IKK1 complex also phosphorylates the p100 within IκBδ, resulting in its partial degradation and releasing bound NFκB dimers for nuclear localization and gene activation. (b) Diagram of the regulatory logic of the noncanonical NFκB signaling network. Noncanonical signals activate NIK/IKK1 that suppresses IκBδ and activates processing of p100 into p52. The suppression of IκBδ that was sequestering preexisting NFκB dimers results in nuclear localization of NFκB and early‐phase gene expression. NIK‐dependent p100 processing results in p52 production and the formation of new RelB:p52 dimers that can activate a late‐phase gene expression response.
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Jens Nielsen

Jens Nielsen
is a Professor in the Department of Biology and Biological Engineering at Chalmers University of Technology in Göteborg, Sweden. His research focus is on systems biology of metabolism. The yeast Saccharomyces cerevisiae is the lab’s key organism for experimental research, but they also work with Aspergilli oryzae.

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