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

Roland Hjerpe, Yann Thomas, Jesse Chen, Aleksandra Zemla, Siobhan Curran, Natalia Shpiro, Lawrence R. Dick, Thimo Kurz (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    69 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)927-936
    Number of pages10
    JournalBiochemical Journal
    Volume441
    Issue number3
    DOIs
    Publication statusPublished - 1 Feb 2012

    Keywords

    • bortezomib
    • MG132
    • MLN4924
    • neural-precursor-cell-expressed developmentally down-regulated 8 (NEDD8)-activating enzyme (NAE)
    • proteasome
    • ubiquitin-activating enzyme
    • TRANSCRIPTIONAL ACTIVITY
    • CULLIN NEDDYLATION
    • E3 LIGASE
    • PROTEIN
    • PATHWAY
    • E1
    • CONJUGATION
    • PROTEASOME
    • INHIBITOR
    • CANCER

    Cite this

    Hjerpe, R., Thomas, Y., Chen, J., Zemla, A., Curran, S., Shpiro, N., Dick, L. R., & Kurz, T. (2012). Changes in the ratio of free NEDD8 to ubiquitin triggers NEDDylation by ubiquitin enzymes. Biochemical Journal, 441(3), 927-936. https://doi.org/10.1042/BJ20111671