HMG-CoA reductase is an ER resident protein required for cholesterol biosynthesis whose selective degradation occurs in a regulated manner in both mammalian cells and in yeast. The investigator, who as a postdoc first demonstrated HMGCoA regulated degradation in yeast, proposes here to pursue a combination of genetic, cell biological and biochemical investigations of HMG CoA reductase degradation in yeast. The investigator has identified a class of genes called HRD (HMGCoA reductase degradation genes) which is required for the regulated degradation of the Hmg2p isozyme in yeast, and he now proposes to test and refine the hypotheses he has developed. One of these genes encodes a subunit of the proteasome, implicating the proteasome in the degradation of ER proteins. The other two genes are novel but have homologs in existing databases. Specifically the aims are: (1) to perform a complete dissection of Hmg2p sequence determinants responsible for regulated degradation (2) to learn the critical features of the three HRD genes and proteins, including functional specificity, cellular location and biochemical properties (3) to test the involvement of the proteasome and ubiquitination in the HRD pathway, and (4) to discover new genes involved in the regulated degradation of Hmg2p.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK051996-03
Application #
2856796
Study Section
Molecular Cytology Study Section (CTY)
Program Officer
Haft, Carol R
Project Start
1997-01-01
Project End
2001-12-31
Budget Start
1999-01-15
Budget End
1999-12-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Neal, Sonya; Jaeger, Philipp A; Duttke, Sascha H et al. (2018) The Dfm1 Derlin Is Required for ERAD Retrotranslocation of Integral Membrane Proteins. Mol Cell 69:306-320.e4
Theesfeld, Chandra L; Hampton, Randolph Y (2013) Insulin-induced gene protein (INSIG)-dependent sterol regulation of Hmg2 endoplasmic reticulum-associated degradation (ERAD) in yeast. J Biol Chem 288:8519-30
Hampton, Randolph Y; Sommer, Thomas (2012) Finding the will and the way of ERAD substrate retrotranslocation. Curr Opin Cell Biol 24:460-6
Theesfeld, Chandra L; Pourmand, Deeba; Davis, Talib et al. (2011) The sterol-sensing domain (SSD) directly mediates signal-regulated endoplasmic reticulum-associated degradation (ERAD) of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase isozyme Hmg2. J Biol Chem 286:26298-307
Heck, Jarrod W; Cheung, Samantha K; Hampton, Randolph Y (2010) Cytoplasmic protein quality control degradation mediated by parallel actions of the E3 ubiquitin ligases Ubr1 and San1. Proc Natl Acad Sci U S A 107:1106-11
Hampton, Randolph Y; Garza, Renee M (2009) Protein quality control as a strategy for cellular regulation: lessons from ubiquitin-mediated regulation of the sterol pathway. Chem Rev 109:1561-74
Garza, Renee M; Sato, Brian K; Hampton, Randolph Y (2009) In vitro analysis of Hrd1p-mediated retrotranslocation of its multispanning membrane substrate 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase. J Biol Chem 284:14710-22
Garza, Renee M; Tran, Peter N; Hampton, Randolph Y (2009) Geranylgeranyl pyrophosphate is a potent regulator of HRD-dependent 3-Hydroxy-3-methylglutaryl-CoA reductase degradation in yeast. J Biol Chem 284:35368-80
Sato, Brian K; Schulz, Daniel; Do, Phong H et al. (2009) Misfolded membrane proteins are specifically recognized by the transmembrane domain of the Hrd1p ubiquitin ligase. Mol Cell 34:212-22
Federovitch, Christine M; Jones, Ying Z; Tong, Amy H et al. (2008) Genetic and structural analysis of Hmg2p-induced endoplasmic reticulum remodeling in Saccharomyces cerevisiae. Mol Biol Cell 19:4506-20

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