Nuclear ubiquitin ligases, NF-kappaB degradation, and the control of inflammation.
Transcriptional control of the vast majority of genes involved in the inflammatory response requires the nuclear factor kappaB (NF-kappaB) family of transcription factors. Stimulation and termination of NF-kappaB activity are subject to stringent spatiotemporal control. According to the classical model of NF-kappaB regulation, both activation and termination mechanisms are centered on inhibitor of NF-kappaB (IkappaB) proteins. Whereas activation of NF-kappaB requires degradation of the IkappaBs, the main mechanism responsible for termination of NF-kappaB activity is the resynthesis of a specific IkappaB, IkappaBalpha, which sequesters NF-kappaB dimers in the nucleus and translocates them to the cytoplasm in an inactive form. Studies now show that an additional mechanism that is required to prevent the uncontrolled activity of NF-kappaB proteins is their nuclear degradation. At least two E3 ubiquitin ligases, one of which seems to be essential for control of nuclear NF-kappaB p65 (also known as RelA) in myeloid cells, have been identified. Moreover, additional evidence indicates that individual NF-kappaB dimers with particular activating or repressive properties may be differentially controlled by nuclear degradation, thus paving the way for the exploitation of NF-kappaB degradation pathways for therapeutic purposes.
Natoli
Gioacchino
G
Department of Experimental Oncology, European Institute of Oncology (IEO), IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy. gioacchino.natoli@ifom-ieo-campus.it
Chiocca
Susanna
S
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002467:Cell Nucleus / Q000201:enzymology*; D019281:Dimerization; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D007249:Inflammation / Q000201:enzymology / Q000628:therapy; D022423:Myeloid Cells / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D051996:Transcription Factor RelA / Q000378:metabolism*; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D044767:Ubiquitin-Protein Ligases