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J. Biol. Chem., Vol. 283, Issue 24, 16622-16631, June 13, 2008

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The COP9/Signalosome Increases the Efficiency of von Hippel-Lindau Protein Ubiquitin Ligase-mediated Hypoxia-inducible Factor- Ubiquitination^*

Yasuhiro Miyauchi, Michiko Kato, Fuminori Tokunaga, and Kazuhiro Iwai^¶1

From the Department of Molecular Cell Biology, Graduate School of Medicine, Osaka City University, Abeno-ku, Osaka 545-8585, Japan, Core Research for Evolutional Science and Technology, Japan Science Technology Corporation, Kawaguchi, Saitama 332-0012, Japan, and ^¶Department of Biophysics and Biochemistry, Graduate School of Medicine and Cell Biology and Metabolism Group, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan

Oxygen-dependent ubiquitination of the -subunit of hypoxia-inducible factor (HIF-) 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-1 degradation by promoting the dissociation of HIF-1 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.

Received for publication, December 31, 2007 , and in revised form, April 17, 2008.

^* This work was supported in part by grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to K. I.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–6.

¹ To whom correspondence should be addressed: Dept. of Biophysics and Biochemistry, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Fax: 81-6-6879-3429; E-mail: kiwai{at}cellbio.med.osaka-u.ac.jp.

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