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Molecular and Cellular Biology, January 2004, p. 475-486, Vol. 24, No. 1
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.1.475-486.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Dual Effects of IB Kinase ß-Mediated Phosphorylation on p105 Fate: SCF^ß-TrCP-Dependent Degradation and SCF^ß-TrCP-Independent Processing

Shai Cohen,^1,2 Hillit Achbert-Weiner,¹ and Aaron Ciechanover^1*

Department of Biochemistry and the Rappaport Family Institute for Research in the Medical Sciences, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096,¹ Department of Internal Medicine A, Lady Davis/"Carmel" Medical Center, Haifa 34362, Israel²

Received 19 May 2003/ Returned for modification 11 July 2003/ Accepted 1 October 2003

Processing of the p105 NF-B precursor to yield the p50 active subunit is a unique and rare case in which the ubiquitin system is involved in limited processing rather than in complete destruction of its target. The mechanisms involved in this process are largely unknown, although a glycine repeat in the middle of p105 has been identified as a processing stop signal. IB kinase (IKK)ß-mediated phosphorylation at the C-terminal domain with subsequent recruitment of the SCF^ß-TrCP ubiquitin ligase leads to accelerated processing and degradation of the precursor, yet the roles that the kinase and ligase play in each of these two processes have not been elucidated. Here we demonstrate that IKKß has two distinct functions: (i) stimulation of degradation and (ii) stimulation of processing. IKKß-induced degradation is dependent on SCF^ß-TrCP, which acts through multiple lysine residues in the IB domain. In contrast, IKKß-induced processing of p105 is ß-transduction repeat-containing protein (ß-TrCP) independent, as it is not affected by expression of a dominant-negative ß-TrCP or following its silencing by small inhibitory RNA. Furthermore, removal of all 30 lysine residues from IB results in complete inhibition of IKK-dependent degradation but has no effect on IKK-dependent processing. Yet processing still requires the activity of the ubiquitin system, as it is inhibited by dominant-negative UbcH5a. We suggest that IKKß mediates its two distinct effects by affecting, directly and indirectly, two different E3s.

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* Corresponding author. Mailing address: Department of Biochemistry, Faculty of Medicine, Technion-Israel Institute of Technology, P.O. Box 9649, Haifa 31096, Israel. Phone: 972-4-829-5356. Fax: 972-4-851-3922. E-mail: c_tzachy{at}netvision.net.il.

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Molecular and Cellular Biology, January 2004, p. 475-486, Vol. 24, No. 1
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.1.475-486.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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