Geranylgeranyl Pyrophosphate Is a Potent Regulator of HRD-dependent 3-Hydroxy-3-methylglutaryl-CoA Reductase Degradation in Yeast

Garza, Renee M.; Tran, Peter; Hampton, Randolph Y.

doi:10.1074/jbc.m109.023994

Cited by 58 publications

(94 citation statements)

References 28 publications

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“…Interestingly, in a recent study Garza et al (59) have demonstrated that degradation of Hmg2p in Saccharomyces cerevisiae is stimulated by GGPP rather than GGOH, and that GGPP is involved in Hmg2p ubiquitylation but not dislocation. However, in the yeast, prevention of protein geranylgeranylation did not hamper the effect of GGPP, indicating that prenylated protein(s) is(are) not involved in Hmg2p turnover (59). Although these results appear to contrast the data presented here, it should be emphasized that Hmg2p stability in yeast is controlled mainly by FPP-derived nonsterol (GGPP) rather than by sterols (59,60).…”

Section: Discussioncontrasting

confidence: 56%

“…However, in the yeast, prevention of protein geranylgeranylation did not hamper the effect of GGPP, indicating that prenylated protein(s) is(are) not involved in Hmg2p turnover (59). Although these results appear to contrast the data presented here, it should be emphasized that Hmg2p stability in yeast is controlled mainly by FPP-derived nonsterol (GGPP) rather than by sterols (59,60). Thus, unlike the mammalian reductase, degradation of Hmg2p in yeast does not involve co-signaling by different MVA-derived metabolites, and GGPP may fulfill all the requirements as a metabolic degradation signal.…”

Section: Discussioncontrasting

confidence: 56%

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Metabolically Regulated Endoplasmic Reticulum-associated Degradation of 3-Hydroxy-3-methylglutaryl-CoA Reductase

Leichner

Avner

Harats

et al. 2011

Journal of Biological Chemistry

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In mammalian cells, the enzyme 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGR), which catalyzes the rate-limiting step in the mevalonate pathway, is ubiquitylated and degraded by the 26 S proteasome when mevalonate-derived metabolites accumulate, representing a case of metabolically regulated endoplasmic reticulum-associated degradation (ERAD). Here, we studied which mevalonate-derived metabolites signal for HMGR degradation and the ERAD step(s) in which these metabolites are required. In HMGR-deficient UT-2 cells that stably express HMGal, a chimeric protein between ␤-galactosidase and the membrane region of HMGR, which is necessary and sufficient for the regulated ERAD, we tested inhibitors specific to different steps in the mevalonate pathway. We found that metabolites downstream of farnesyl pyrophosphate but upstream to lanosterol were highly effective in initiating ubiquitylation, dislocation, and degradation of HMGal. Similar results were observed for endogenous HMGR in cells that express this protein. Ubiquitylation, dislocation, and proteasomal degradation of HMGal were severely hampered when production of geranylgeranyl pyrophosphate was inhibited. Importantly, inhibition of protein geranylgeranylation markedly attenuated ubiquitylation and dislocation, implicating for the first time a geranylgeranylated protein(s) in the metabolically regulated ERAD of HMGR.Mammalian cells satisfy most of their cholesterol requirements through receptor-mediated endocytosis of cholesterolrich plasma lipoproteins. However, when exogenous cholesterol supply is short, or when there is an increased demand for particular nonsterol isoprenoid(s), cells up-regulate the activity of the mevalonate (MVA) 3 pathway ( Fig. 1), in which sterols and essential MVA-derived nonsterol isoprenoids are produced (1, 2). Intracellular MVA levels are finely tuned and tightly regulated by a feedback mechanism that governs the rate of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reduction into MVA, the major rate-limiting step for the entire pathway (3, 4). This reaction is catalyzed by HMG-CoA reductase (HMGR), an integral glycoprotein resident to the endoplasmic reticulum (ER). Each of the 97-kDa subunits of HMGR is embedded in the ER membrane via a ϳ350 residue N-terminal noncatalytic region that spans the membrane 8 times (5-7), whereas the rest of the polypeptide faces the cytosol where it tetramerizes to form the active sites of the enzyme (5, 8, 9). To allow sufficient production of isoprenoids yet avoid overaccumulation of potentially toxic products, the activity of HMGR is stringently controlled and varies according to the cellular needs for sterol and the nonsterol products. HMGR activity increases when cells are starved for cholesterol or MVA. Conversely, abundant cholesterol and/or MVA acutely suppress the enzyme (4, 10). At the post-translational level, regulation of HMGR mainly involves modulation of its stability. Thus, in cells deprived of sterols and/or MVA, HMGR is a rather stable protein that turns over with a half-l...

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Section: Discussioncontrasting

confidence: 56%

Section: Discussioncontrasting

confidence: 56%

Metabolically Regulated Endoplasmic Reticulum-associated Degradation of 3-Hydroxy-3-methylglutaryl-CoA Reductase

Leichner

Avner

Harats

et al. 2011

Journal of Biological Chemistry

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“…Our more recent work has shown that geranylgeranyl pyrophosphate (GGPP), which is structurally analogous to FPP but with 20 carbons, is the likely bona fide signal (see Fig. 1) (22). In addition, we have shown that an oxysterol signal appears to modulate the degradation of Hmg2 as well; increased levels of certain oxysterols enhance the degradation rate controlled by endogenous levels of the FPP-derived signal (23).…”

mentioning

confidence: 83%

“…22. Following treatment with drugs or control treatment, the fluorescence of 10,000 cells in each sample was measured.…”

Section: Methodsmentioning

confidence: 99%

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The Sterol-sensing Domain (SSD) Directly Mediates Signal-regulated Endoplasmic Reticulum-associated Degradation (ERAD) of 3-Hydroxy-3-methylglutaryl (HMG)-CoA Reductase Isozyme Hmg2

Theesfeld¹,

Pourmand²,

Davis

et al. 2011

Journal of Biological Chemistry

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The sterol-sensing domain (SSD) is a conserved motif in membrane proteins responsible for sterol regulation. Mammalian proteins SREBP cleavage-activating protein (SCAP) and HMG-CoA reductase (HMGR) both possess SSDs required for feedback regulation of sterol-related genes and sterol synthetic rate. Although these two SSD proteins clearly sense sterols, the range of signals detected by this eukaryotic motif is not clear. The yeast HMG-CoA reductase isozyme Hmg2, like its mammalian counterpart, undergoes endoplasmic reticulum (ER)-associated degradation that is subject to feedback control by the sterol pathway. The primary degradation signal for yeast Hmg2 degradation is the 20-carbon isoprene geranylgeranyl pyrophosphate, rather than a sterol. Nevertheless, the Hmg2 protein possesses an SSD, leading us to test its role in feedback control of Hmg2 stability. We mutated highly conserved SSD residues of Hmg2 and evaluated regulated degradation. Our results indicated that the SSD was required for sterol pathway signals to stimulate Hmg2 ER-associated degradation and was employed for detection of both geranylgeranyl pyrophosphate and a secondary oxysterol signal. Our data further indicate that the SSD allows a signal-dependent structural change in Hmg2 that promotes entry into the ER degradation pathway. Thus, the eukaryotic SSD is capable of significant plasticity in signal recognition or response. We propose that the harnessing of cellular quality control pathways to bring about feedback regulation of normal proteins is a unifying theme for the action of all SSDs.

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Insight into yeast: A study model of lipid metabolism and terpenoid biosynthesis

2014

Biotech and App Biochem

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With the development of transcriptomics, metabolomics, proteomics, and mathematical modeling, yeast Saccharomyces cerevisiae is recently considered as a model studying strain by biologists who try to reveal the mystery of microorganic metabolism or develop heterologous pharmaceutical and economic products. Among S. cerevisiae metabolic research, lipid metabolism always attracts great interest because of its dominant role in cell physiology. Related researchers have developed multiple functions from cell membrane component such as adjustment to changing environment and impact on protein folding. Nowadays, many common human diseases such as diabetes mellitus, Alzheimer's disease, obesity, and atherosclerosis are related to lipid metabolism, which makes the study of lipids a desperate need. In addition to lipid metabolism, the study of the native mevalonic acid (MVA) pathway in S. cerevisiae has increased exponentially because of its huge potential to produce economically important products terpenoids. With the progress of technology in gene engineering and metabolic engineering, more and more biosynthetic pathways will be developed and put into industrial application.

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Geranylgeranyl Pyrophosphate Is a Potent Regulator of HRD-dependent 3-Hydroxy-3-methylglutaryl-CoA Reductase Degradation in Yeast

Cited by 58 publications

References 28 publications

Metabolically Regulated Endoplasmic Reticulum-associated Degradation of 3-Hydroxy-3-methylglutaryl-CoA Reductase

Metabolically Regulated Endoplasmic Reticulum-associated Degradation of 3-Hydroxy-3-methylglutaryl-CoA Reductase

The Sterol-sensing Domain (SSD) Directly Mediates Signal-regulated Endoplasmic Reticulum-associated Degradation (ERAD) of 3-Hydroxy-3-methylglutaryl (HMG)-CoA Reductase Isozyme Hmg2

Insight into yeast: A study model of lipid metabolism and terpenoid biosynthesis

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