UBXD7 binds multiple ubiquitin ligases and implicates p97 in HIF1 alpha turnover

Gabriela Alexandru, Johannes Graumann, Geoffrey T. Smith, Natalie J. Kolawa, Ruihua Fang, Raymond J. Deshaies

    Research output: Contribution to journalArticlepeer-review

    229 Citations (Scopus)

    Abstract

    p97 is an ATP-dependent chaperone that plays an important role in endoplasmic reticulum-associated degradation but whose connections to turnover of soluble proteins remain sparse. Binding of p97 to substrates is mediated by cofactors that contain ubiquitin-binding domains. We employed "network proteomics'' to show that p97 assembles with all of the 13 mammalian UBX-domain proteins. The UBX proteins that bind ubiquitin conjugates also interact with dozens of E3 ubiquitin ligases, only one of which had been previously linked to p97. In particular, UBXD7 links p97 to the ubiquitin ligase CUL2/VHL and its substrate hypoxia-inducible factor 1 alpha (HIF1 alpha). Depletion of p97 leads to accumulation of endogenous HIF1 alpha and increased expression of a HIF1 alpha target gene. The large number of ubiquitin ligases found associated with UBX proteins suggests that p97 plays a far broader role than previously anticipated in the global regulation of protein turnover.

    Original languageEnglish
    Pages (from-to)804-816
    Number of pages13
    JournalCell
    Volume134
    Issue number5
    DOIs
    Publication statusPublished - 5 Sep 2008

    Keywords

    • AAA-ATPASE CDC48/P97
    • RETICULUM-ASSOCIATED DEGRADATION
    • VALOSIN-CONTAINING PROTEIN
    • POLYUBIQUITIN CHAINS
    • TRANSCRIPTION FACTOR
    • SELECTIVE CHAPERONE
    • MEMBRANE-FUSION
    • 26S PROTEASOME
    • ER
    • COMPLEX

    Cite this