Control of IkappaBalpha proteolysis by the ubiquitin-proteasome pathway.
It has recently been determined that the proteolytic destruction of IkappaB (inhibitor of NF-kappaB) by the ubiquitin-proteasome system plays a key role in the immediate elimination of IkappaB from the IkappaB-(NF-kappaB) complex which allows nuclear translocation of free NF-kappaB, thus leading to activation of a multitude of target genes. The SCF(Fbw1) (composed of Skp1, Cul-1, Roc1, and Fbw1) complex, identified as an IkappaBalpha-E3 ligase, binds and ubiquitylates IkappaBalpha phosphorylated by IkappaB kinase that has been activated in response to extracellular signals. The generating poly-ubiquitin chain is finally recognized by the 26S proteasome for ultimate degradation. In this NF-kappaB signalling pathway, it becomes clear that the SCF(Fbw1) activity is enhanced by a ubiquitin-like protein NEDD8 (equivalent to Rub1) that modifies Cul-1 in a manner analogous to ubiquitylation, and consequently, IkappaBalpha proteolysis is induced. NEDD8 is a new regulator of the SCF ubiquitin-ligase, functioning as a covalent modifier for proteolytic targeting at a physiological level.
Tanaka
K
K
The Tokyo Metropolitan Institute of Medical Science, and CREST, Japan Science and Technology Corporation (JST), 113-8613, Tokyo, Japan. tanakak@rinshoken.or.jp
Kawakami
T
T
Tateishi
K
K
Yashiroda
H
H
Chiba
T
T
D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D009097:Multienzyme Complexes / Q000378:metabolism; D000075687:NEDD8 Protein; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism*; D010453:Peptide Synthases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases; D015398:Signal Transduction / Q000502:physiology; D014452:Ubiquitins / Q000378:metabolism*
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D009097:Multienzyme Complexes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D014452:Ubiquitins; D000072000:NF-KappaB Inhibitor alpha; D044843:SKP Cullin F-Box Protein Ligases; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D010453:Peptide Synthases