The COP9/signalosome increases the efficiency of von Hippel-Lindau protein ubiquitin ligase-mediated hypoxia-inducible factor-alpha ubiquitination.
Oxygen-dependent ubiquitination of the alpha-subunit of hypoxia-inducible factor (HIF-alpha) by the (von Hippel-Lindau protein)-Elongin B/C-Cullin2-Rbx1 (VBC-Cul2) ubiquitin ligase, a member of the cullin-RING ubiquitin ligases (CRLs), plays a central role in controlling oxygen metabolism. Nedd8 conjugation of cullins enhances the ligase activity of CRLs, and the COP9/signalosome (CSN) enhances the degradation of several CRL substrates, although it removes Nedd8 from cullins. Here we demonstrate that CSN increased the efficiency of the VBC-Cul2 complex for recognizing and ubiquitinating substrates by facilitating the dissociation of ubiquitinated substrates from the pVHL subunit of the complex. Moreover CSN enhanced HIF-1alpha degradation by promoting the dissociation of HIF-1alpha from pVHL in cells. The length of the polyubiquitin chain conjugated to the substrate appeared to be involved in CSN-mediated dissociation of the substrate from pVHL. In contrast to other mechanisms underlying CSN-mediated activation of CRLs, the dissociation of ubiquitinated substrates from pVHL did not require the deneddylation activity of CSN, implying that CSN enhances degradation of CRL substrates by multiple mechanisms.
Miyauchi
Yasuhiro
Y
Department of Molecular Cell Biology, Graduate School of Medicine, Osaka City University, Abeno-ku, Osaka 545-8585, Japan.
Kato
Michiko
M
Tokunaga
Fuminori
F
Iwai
Kazuhiro
K
D000075686:COP9 Signalosome Complex; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007700:Kinetics; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism*; D009154:Mutation; D010447:Peptide Hydrolases / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D025801:Ubiquitin / Q000737:chemistry; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D046912:Multiprotein Complexes; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex