Changes in the ratio of free NEDD8 to ubiquitin triggers NEDDylation by ubiquitin enzymes

Hjerpe, R., Thomas, Y., Chen, J., Zemla, A., Curran, S., Shpiro, N., Dick, L. R. and Kurz, T. (2012) Changes in the ratio of free NEDD8 to ubiquitin triggers NEDDylation by ubiquitin enzymes. Biochemical Journal, 441(3), pp. 927-939. (doi: 10.1042/BJ20111671) (PMID:22004789) (PMCID:PMC3280039)

Abstract

Ubiquitin and UBL (ubiquitin-like) modifiers are small proteins that covalently modify other proteins to alter their properties or behaviours. Ubiquitin modification (ubiquitylation) targets many substrates, often leading to their proteasomal degradation. NEDD8 (neural-precursor-cell-expressed developmentally down-regulated 8) is the UBL most closely related to ubiquitin, and its best-studied role is the activation of CRLs (cullin-RING ubiquitin ligases) by its conjugation to a conserved C-terminal lysine residue on cullin proteins. The attachment of UBLs requires three UBL-specific enzymes, termed E1, E2 and E3, which are usually well insulated from parallel UBL pathways. In the present study, we report a new mode of NEDD8 conjugation (NEDDylation) whereby the UBL NEDD8 is linked to proteins by ubiquitin enzymes in vivo. We found that this atypical NEDDylation is independent of classical NEDD8 enzymes, conserved from yeast to mammals, and triggered by an increase in the NEDD8 to ubiquitin ratio. In cells, NEDD8 overexpression leads to this type of NEDDylation by increasing the concentration of NEDD8, whereas proteasome inhibition has the same effect by depleting free ubiquitin. We show that bortezomib, a proteasome inhibitor used in cancer therapy, triggers atypical NEDDylation in tissue culture, which suggests that a similar process may occur in patients receiving this treatment.

• Item Type: Articles
• Additional Information: This work was supported by an ERC Young Investigator Grant (to T.K.), by a European Regional Development Fund Grant for an Innovation Pipeline for Translational Science [grant number LUPS/ERDF/2008/2/1/0429] and by a grant from the Scottish government to the Scottish Institute for Cell Signalling.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Kurz, Dr Thimo
• Authors: Hjerpe, R., Thomas, Y., Chen, J., Zemla, A., Curran, S., Shpiro, N., Dick, L. R., and Kurz, T.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Biochemical Journal
• Publisher: Portland Press
• ISSN: 0264-6021
• ISSN (Online): 1470-8728
• Published Online: 17 October 2011
• Copyright Holders: Copyright © 2012 The Authors
• First Published: First published in Biochemical Journal 441(3): 927-939
• Publisher Policy: Reproduced under a Creative Commons License