Key Points
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NF-κB (nuclear factor-κB) activation is mediated by two main signalling pathways, the canonical and non-canonical pathways, which differ in both signalling mechanisms and biological functions.
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The canonical NF-κB pathway is stimulated by ligands of diverse immune receptors and involves the rapid and transient activation of IκB kinase (IKK), IKK-mediated IκBα phosphorylation, and subsequent IκBα degradation and nuclear translocation of canonical NF-κB members, including p50, RELA and c-REL.
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The non-canonical NF-κB pathway selectively responds to signals from a subset of tumour necrosis factor receptor (TNFR) superfamily members and involves slow and persistent activation of NF-κB-inducing kinase (NIK), NIK-mediated p100 phosphorylation, and subsequent p100 processing and nuclear translocation of non-canonical NF-κB members, including p52 and RELB.
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The non-canonical NF-κB pathway is tightly controlled by ubiquitin-dependent degradation of NIK mediated by an E3 ubiquitin ligase complex composed of cIAP family members, TNFR-associated factor 2 (TRAF2) and TRAF3; activation of non-canonical NF-κB involves signal-induced disruption of the cIAP E3 complex, typically via degradation of TRAF3, and accumulation of NIK.
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The non-canonical NF-κB pathway regulates important aspects of immune functions, including lymphoid organ development, the cross-priming function of dendritic cells, B cell survival and germinal centre reactions, generation and maintenance of effector and memory T cells, and antiviral innate immunity.
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The non-canonical NF-κB pathway is involved in various inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus, kidney inflammation and injury, metabolic inflammation, and central nervous system inflammation.
Abstract
The nuclear factor-κB (NF-κB) family of transcription factors is activated by canonical and non-canonical signalling pathways, which differ in both signalling components and biological functions. Recent studies have revealed important roles for the non-canonical NF-κB pathway in regulating different aspects of immune functions. Defects in non-canonical NF-κB signalling are associated with severe immune deficiencies, whereas dysregulated activation of this pathway contributes to the pathogenesis of various autoimmune and inflammatory diseases. Here we review the signalling mechanisms and the biological function of the non-canonical NF-κB pathway. We also discuss recent progress in elucidating the molecular mechanisms regulating non-canonical NF-κB pathway activation, which may provide new opportunities for therapeutic strategies.
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Acknowledgements
Work in the author's laboratory is supported by grants from the US National Institutes of Health (AI057555, AI064639, GM84459 and AI104519) and the Cancer Prevention Research Institute of Texas (RP140244 and RP150235).
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Glossary
- Tumour necrosis factor receptor (TNFR) superfamily
-
A large family of cytokine receptors that are engaged by members of the TNF superfamily of cytokines and mediate signal transduction.
- Epidermal growth factor receptor
-
(EGFR). A receptor tyrosine kinase that responds to the growth factor EGF and mediates cell growth and survival by triggering several intracellular signalling pathways.
- p63
-
A p53 homologue produced as two main isoforms, TAp63 and ΔNp63, with ΔNp63 lacking the N-terminal typical transactivation domain and functioning as a dominant-negative form to promote oncogenesis.
- Tripartite motif-containing protein 29
-
(TRIM29). A member of the TRIM family implicated in oncogenesis.
- Stromal organizer cells
-
Matrix cells of mesenchymal origin that characteristically express the cell adhesion molecules VCAM1 and ICAM1 and the TNFR member LTβR and are required for lymphoid organ development.
- Cross-priming
-
A mechanism of CD8+ T cell priming, in which antigen-presenting cells take up extracellular antigens, process and present them with MHC class I molecules to CD8+ T cells.
- Small interfering RNA
-
(siRNA). Short double-stranded RNA molecules, typically 20–25 bp in length, which bind to and induce degradation of mRNAs with complementary sequences, thereby interfering with production of the corresponding proteins.
- Common variable immunodeficiency
-
A frequently diagnosed and heterogeneous type of primary immunodeficiency characterized by low to undetectable levels of antibodies and increased susceptibility to infections.
- Experimental autoimmune encephalomyelitis
-
(EAE). A commonly used animal model of the autoimmune neuroinflammatory disease multiple sclerosis, characterized by infiltration of the central nervous system with T cells and monocytes that cause inflammation and demyelination leading to limb paralysis.
- Rheumatoid arthritis
-
(RA). An autoimmune disease characterized by chronic inflammation in the joints and destruction of cartilage and bone.
- Systemic lupus erythematosus
-
(SLE). An autoimmune disease characterized by chronic inflammation throughout the body, causing tissue damage in multiple organs.
- SMAC mimetics
-
A class of small-molecule compounds that bind to and antagonize cIAP by mimicking the endogenous IAP antagonist SMAC.
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Sun, SC. The non-canonical NF-κB pathway in immunity and inflammation. Nat Rev Immunol 17, 545–558 (2017). https://doi.org/10.1038/nri.2017.52
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DOI: https://doi.org/10.1038/nri.2017.52
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