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RY Hampton, RG Gardner and J Rine
Department of Biology, University of California, San Diego, La Jolla 92093-0116, USA.
3-hydroxy-3-methylglutaryl-CoA reductase (HMG-R), a key enzyme of sterol synthesis, is an integral membrane protein of the endoplasmic reticulum (ER). In both humans and yeast, HMG-R is degraded at or in the ER. The degradation of HMG-R is regulated as part of feedback control of the mevalonate pathway. Neither the mechanism of degradation nor the nature of the signals that couple the degradation of HMG-R to the mevalonate pathway is known. We have launched a genetic analysis of the degradation of HMG-R in Saccharomyces cerevisiae using a selection for mutants that are deficient in the degradation of Hmg2p, an HMG-R isozyme. The underlying genes are called HRD (pronounced "herd"), for HMG-CoA reductase degradation. So far we have discovered mutants in three genes: HRD1, HRD2, and HRD3. The sequence of the HRD2 gene is homologous to the p97 activator of the 26S proteasome. This p97 protein, also called TRAP-2, has been proposed to be a component of the mature 26S proteasome. The hrd2-1 mutant had numerous pleiotropic phenotypes expected for cells with a compromised proteasome, and these phenotypes were complemented by the human TRAP-2/p97 coding region. In contrast, HRD1 and HRD3 genes encoded previously unknown proteins predicted to be membrane bound. The Hrd3p protein was homologous to the Caenorhabditis elegans sel-1 protein, a negative regulator of at least two different membrane proteins, and contained an HRD3 motif shared with several other proteins. Hrd1p had no full-length homologues, but contained an H2 ring finger motif. These data suggested a model of ER protein degradation in which the Hrd1p and Hrd3p proteins conspire to deliver HMG-R to the 26S proteasome. Moreover, our results lend in vivo support to the proposed role of the p97/TRAP-2/Hrd2p protein as a functionally important component of the 26S proteasome. Because the HRD genes were required for the degradation of both regulated and unregulated substrates of ER degradation, the HRD genes are the agents of HMG-R degradation but not the regulators of that degradation.
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D. J. Katzmann, E. A. Epping, and W. S. Moye-Rowley Mutational Disruption of Plasma Membrane Trafficking of Saccharomyces cerevisiae Yor1p, a Homologue of Mammalian Multidrug Resistance Protein Mol. Cell. Biol., April 1, 1999; 19(4): 2998 - 3009. [Abstract] [Full Text] [PDF]
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J. L. Brodsky, E. D. Werner, M. E. Dubas, J. L. Goeckeler, K. B. Kruse, and A. A. McCracken The Requirement for Molecular Chaperones during Endoplasmic Reticulum-associated Protein Degradation Demonstrates That Protein Export and Import Are Mechanistically Distinct J. Biol. Chem., February 5, 1999; 274(6): 3453 - 3460. [Abstract] [Full Text] [PDF]
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X. Xiong, E. Chong, and W. R. Skach Evidence That Endoplasmic Reticulum (ER)-associated Degradation of Cystic Fibrosis Transmembrane Conductance Regulator Is Linked to Retrograde Translocation from the ER Membrane J. Biol. Chem., January 29, 1999; 274(5): 2616 - 2624. [Abstract] [Full Text] [PDF]
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E. Z. Du, J. F. Fleming, S.-L. Wang, G. M. Spitsen, and R. A. Davis Translocation-arrested Apolipoprotein B Evades Proteasome Degradation via a Sterol-sensitive Block in Ubiquitin Conjugation J. Biol. Chem., January 15, 1999; 274(3): 1856 - 1862. [Abstract] [Full Text] [PDF]
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K Romisch Surfing the Sec61 channel: bidirectional protein translocation across the ER membrane J. Cell Sci., January 12, 1999; 112(23): 4185 - 4191. [Abstract] [PDF]
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R. Plemper, J Bordallo, P. Deak, C Taxis, R Hitt, and D. Wolf Genetic interactions of Hrd3p and Der3p/Hrd1p with Sec61p suggest a retro-translocation complex mediating protein transport for ER degradation J. Cell Sci., January 11, 1999; 112(22): 4123 - 4134. [Abstract] [PDF]
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J. A. Johnston, C. L. Ward, and R. R. Kopito Aggresomes: A Cellular Response to Misfolded Proteins J. Cell Biol., December 28, 1998; 143(7): 1883 - 1898. [Abstract] [Full Text] [PDF]
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P. Breuer and T. Braulke Stabilization of Mutant 46-kDa Mannose 6-Phosphate Receptors by Proteasomal Inhibitor Lactacystin J. Biol. Chem., December 11, 1998; 273(50): 33254 - 33258. [Abstract] [Full Text] [PDF]
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R. K. Plemper, R. Egner, K. Kuchler, and D. H. Wolf Endoplasmic Reticulum Degradation of a Mutated ATP-binding Cassette Transporter Pdr5 Proceeds in a Concerted Action of Sec61 and the Proteasome J. Biol. Chem., December 4, 1998; 273(49): 32848 - 32856. [Abstract] [Full Text] [PDF]
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Z. Bebok, C. Mazzochi, S. A. King, J. S. Hong, and E. J. Sorscher The Mechanism Underlying Cystic Fibrosis Transmembrane Conductance Regulator Transport from the Endoplasmic Reticulum to the Proteasome Includes Sec61beta and a Cytosolic, Deglycosylated Intermediary J. Biol. Chem., November 6, 1998; 273(45): 29873 - 29878. [Abstract] [Full Text] [PDF]
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D. Loayza, A. Tam, W. K. Schmidt, and S. Michaelis Ste6p Mutants Defective in Exit from the Endoplasmic Reticulum (ER) Reveal Aspects of an ER Quality Control Pathway in Saccharomyces cerevisiae Mol. Biol. Cell, October 1, 1998; 9(10): 2767 - 2784. [Abstract] [Full Text]
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R. Gardner, S. Cronin, B. Leder, J. Rine, and R. Hampton Sequence Determinants for Regulated Degradation of Yeast 3-Hydroxy-3-Methylglutaryl-CoA Reductase, an Integral Endoplasmic Reticulum Membrane Protein Mol. Biol. Cell, September 1, 1998; 9(9): 2611 - 2626. [Abstract] [Full Text]
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T. Moriyama, S. K. Sather, T. P. McGee, and R. D. Simoni Degradation of HMG-CoA Reductase in Vitro. CLEAVAGE IN THE MEMBRANE DOMAIN BY A MEMBRANE-BOUND CYSTEINE PROTEASE J. Biol. Chem., August 21, 1998; 273(34): 22037 - 22043. [Abstract] [Full Text] [PDF]
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K. Meerovitch, S. Wing, and D. Goltzman Proparathyroid Hormone-related Protein Is Associated with the Chaperone Protein BiP and Undergoes Proteasome-mediated Degradation J. Biol. Chem., August 14, 1998; 273(33): 21025 - 21030. [Abstract] [Full Text] [PDF]
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T. Potuschak, S. Stary, P. Schlogelhofer, F. Becker, V. Nejinskaia, and A. Bachmair PRT1 of Arabidopsis thaliana encodes a component of the plant N-end rule pathway PNAS, July 7, 1998; 95(14): 7904 - 7908. [Abstract] [Full Text] [PDF]
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I. Greenwald LIN-12/Notch signaling: lessons from worms and flies Genes & Dev., June 15, 1998; 12(12): 1751 - 1762. [Full Text]
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M. H. Glickman, D. M. Rubin, V. A. Fried, and D. Finley The Regulatory Particle of the Saccharomyces cerevisiae Proteasome Mol. Cell. Biol., June 1, 1998; 18(6): 3149 - 3162. [Abstract] [Full Text]
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T. Suzuki, Q. Yan, and W. J. Lennarz Complex, Two-way Traffic of Molecules Across the Membrane of the Endoplasmic Reticulum J. Biol. Chem., April 24, 1998; 273(17): 10083 - 10086. [Full Text] [PDF]
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M. de Virgilio, H. Weninger, and N. E. Ivessa Ubiquitination Is Required for the Retro-translocation of a Short-lived Luminal Endoplasmic Reticulum Glycoprotein to the Cytosol for Degradation by the Proteasome J. Biol. Chem., April 17, 1998; 273(16): 9734 - 9743. [Abstract] [Full Text] [PDF]
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G. Fenteany and S. L. Schreiber Lactacystin, Proteasome Function, and Cell Fate J. Biol. Chem., April 10, 1998; 273(15): 8545 - 8548. [Full Text] [PDF]
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 J. Galan, B. Cantegrit, C. Garnier, O. Namy, and R. Haguenauer-tsapis `ER degradation' of a mutant yeast plasma membrane protein by the ubiquitin-proteasome pathway FASEB J, March 1, 1998; 12(3): 315 - 323. [Abstract] [Full Text]
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J. Bordallo, R. K. Plemper, A. Finger, and D. H. Wolf Der3p/Hrd1p Is Required for Endoplasmic Reticulum-associated Degradation of Misfolded Lumenal and Integral Membrane Proteins Mol. Biol. Cell, January 1, 1998; 9(1): 209 - 222. [Abstract] [Full Text]
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R. Y. Hampton and H. Bhakta Ubiquitin-mediated regulation of 3-hydroxy-3-methylglutaryl-CoA reductase PNAS, November 25, 1997; 94(24): 12944 - 12948. [Abstract] [Full Text] [PDF]
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C. R. M. Wilkinson, M. Wallace, M. Seeger, W. Dubiel, and C. Gordon Mts4, a Non-ATPase Subunit of the 26 S Protease in Fission Yeast Is Essential for Mitosis and Interacts Directly with the ATPase Subunit Mts2 J. Biol. Chem., October 10, 1997; 272(41): 25768 - 25777. [Abstract] [Full Text] [PDF]
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T. Ravid, R. Doolman, R. Avner, D. Harats, and J. Roitelman The Ubiquitin-Proteasome Pathway Mediates the Regulated Degradation of Mammalian 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase J. Biol. Chem., November 10, 2000; 275(46): 35840 - 35847. [Abstract] [Full Text] [PDF]
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S. Tiwari and A. M. Weissman Endoplasmic Reticulum (ER)-associated Degradation of T Cell Receptor Subunits. INVOLVEMENT OF ER-ASSOCIATED UBIQUITIN-CONJUGATING ENZYMES (E2s) J. Biol. Chem., May 4, 2001; 276(19): 16193 - 16200. [Abstract] [Full Text] [PDF]
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R. G. Gardner, H. Shan, S. P. T. Matsuda, and R. Y. Hampton An Oxysterol-derived Positive Signal for 3-Hydroxy- 3-methylglutaryl-CoA Reductase Degradation in Yeast J. Biol. Chem., March 16, 2001; 276(12): 8681 - 8694. [Abstract] [Full Text] [PDF]
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P. M. Deak and D. H. Wolf Membrane Topology and Function of Der3/Hrd1p as a Ubiquitin-Protein Ligase (E3) Involved in Endoplasmic Reticulum Degradation J. Biol. Chem., March 30, 2001; 276(14): 10663 - 10669. [Abstract] [Full Text] [PDF]
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