Non-canonical NF-κB signaling activation and regulation: principles and perspectives.
Nuclear-factor κB (NF-κB) transcription factors are activated by a wide variety of stimuli in diverse cell types and control key aspects of immune function and development. Receptor-mediated activation of NF-κB appears to occur through two distinct signaling pathways termed as the canonical and non-canonical NF-κB pathways. Although much work has demonstrated the physiological importance of non-canonical NF-κB signaling to immunity and its involvement in diverse pathologies, such as cancers and autoimmune disease, the architecture and regulation of the pathway is only beginning to be understood. The non-canonical pathway appears to be activated by a select set of receptors within the tumor necrosis factor superfamily, and we discuss the molecular mechanisms that connect ligation of these receptors to pathway activation. It has become increasingly clear that the key regulatory step of the pathway involves modulation of the post-translational degradation of NF-κB-inducing kinase (NIK), the central activating kinase of non-canonical NF-κB signaling. How NIK post-translational stability is controlled before and after receptor ligation is an important aspect of understanding non-canonical NF-κB signaling. Furthermore, how release of NF-κB dimers downstream of the pathway's activation is actually connected to its identified physiological and pathological roles is a key remaining question in the field.
Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095, USA.
Bahram
B
Razani
Anna Devi
AD
Reichardt
Genhong
G
Cheng
D000818:Animals; D019281:Dimerization; D004795:Enzyme Stability; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D016328:NF-kappa B; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D018124:Receptors, Tumor Necrosis Factor; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D014409:Tumor Necrosis Factor-alpha; D000097782:NF-kappaB-Inducing Kinase; C090656:TRAF3 protein, human