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Molecular and Cellular Biology, April 2000, p. 2326-2333, Vol. 20, No. 7
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Nedd8 Modification of Cul-1 Activates SCFbeta TrCP-Dependent Ubiquitination of Ikappa Balpha

Margaret A. Read,* James E. Brownell, Tatiana B. Gladysheva, Maria Hottelet, Lana A. Parent, Michael B. Coggins, Jacqueline W. Pierce, Vladimir N. Podust,dagger Rong-Shu Luo, Vincent Chau, and Vito J. Palombella

LeukoSite, Inc., Cambridge, Massachusetts 02139

Received 24 August 1999/Returned for modification 23 September 1999/Accepted 22 December 1999

Regulation of NF-kappa B occurs through phosphorylation-dependent ubiquitination of Ikappa Balpha , which is degraded by the 26S proteasome. Recent studies have shown that ubiquitination of Ikappa Balpha is carried out by a ubiquitin-ligase enzyme complex called SCFbeta TrCP. Here we show that Nedd8 modification of the Cul-1 component of SCFbeta TrCP is important for function of SCFbeta TrCP in ubiquitination of Ikappa Balpha . In cells, Nedd8-conjugated Cul-1 was complexed with two substrates of SCFbeta TrCP, phosphorylated Ikappa Balpha and beta -catenin, indicating that Nedd8-Cul-1 conjugates are part of SCFbeta TrCP in vivo. Although only a minute fraction of total cellular Cul-1 is modified by Nedd8, the Cul-1 associated with ectopically expressed beta TrCP was highly enriched for the Nedd8-conjugated form. Moreover, optimal ubiquitination of Ikappa Balpha required Nedd8 and the Nedd8-conjugating enzyme, Ubc12. The site of Nedd8 ligation to Cul-1 is essential, as SCFbeta TrCP containing a K720R mutant of Cul-1 only weakly supported Ikappa Balpha ubiquitination compared to SCFbeta TrCP containing WT Cul-1, suggesting that the Nedd8 ligation of Cul-1 affects the ubiquitination activity of SCFbeta TrCP. These observations provide a functional link between the highly related ubiquitin and Nedd8 pathways of protein modification and show how they operate together to selectively target the signal-dependent degradation of Ikappa Balpha .

* Corresponding author. Mailing address: Millennium Pharmaceuticals, 38 Sidney St., Cambridge, MA 02139. Phone: (617) 551-3725. Fax: (617) 551-3747. E-mail: mread{at}mpi.com.

dagger Present address: Department of Molecular Biology, Vanderbilt University, Nashville, TN 37235.

Molecular and Cellular Biology, April 2000, p. 2326-2333, Vol. 20, No. 7
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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