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UBXD7 Binds Multiple Ubiquitin Ligases and Implicates p97 in HIF1α Turnover

Alexandru, Gabriela and Graumann, Johannes and Smith, Geoffrey T. and Kolawa, Natalie J. (2008) UBXD7 Binds Multiple Ubiquitin Ligases and Implicates p97 in HIF1α Turnover. Cell, 134 (5). pp. 804-816. ISSN 0092-8674.

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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 1α (HIF1α). Depletion of p97 leads to accumulation of endogenous HIF1α and increased expression of a HIF1α 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.

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Additional Information:Copyright © 2008 Elsevier. Received 2 November 2007; revised 9 April 2008; accepted 25 June 2008. Published: September 4, 2008. Available online 4 September 2008. We thank G. Kleiger and T. Chou for help with gel filtration, J. Quimby for help with DNA cloning, S. Schwarz for advice on cell culture, R. Oania for technical assistance, and S. Buonomo for experimental protocols. We also thank T. Nagase, G. Warren, H. Katoh, and S. Buonomo for plasmids and Millipore, J. Pastorek, S. Pastorekova, and Z. Xia for antibodies. We are grateful to A. Varshavsky and members of the Deshaies' lab for critical reading of the manuscript. G.A. was supported by DRG-1745-02 of the Damon Runyon Cancer Research Foundation and the Howard Hughes Medical Institute (HHMI). R.J.D. is an HHMI Investigator, and this work was funded by HHMI. R.J.D. is a founder, shareholder, and consultant for Proteolix. Supplemental Data include two figures and five tables and can be found with this article online at
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Damon Runyan Cancer Research FoundationDRG-1745-02
Howard Hughes Medical InstituteUNSPECIFIED
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Deposited On:29 Sep 2008 22:50
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