Intracellular degradation of newly synthesized secretory proteins

Bienkowski, Robert S.

doi:10.1042/bj2140001

Cited by 143 publications

(58 citation statements)

References 33 publications

(21 reference statements)

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“…Protein degradation is an essential function that has Mutant, modified, or misassembled proteins all remany roles in all eukaryotic cells (Bienkowski, 1983;quire disposal (Schuller et al, 1992;Tierney et al, 1992; Tsuji et al, 1992; Pearce and Sherman, 1995). Viral invasion strategies can include degradative tactics tCorresponding author.…”

Section: Introductionmentioning

confidence: 99%

Role of 26S proteasome and HRD genes in the degradation of 3-hydroxy-3-methylglutaryl-CoA reductase, an integral endoplasmic reticulum membrane protein.

Hampton

Gardner

Rine

1996

MBoC

528

534

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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. Hrdlp had no full-length homologues, but contained an H2 ring finger motif. These data suggested a model of ER protein degradation in which the Hrdlp 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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Section: Introductionmentioning

confidence: 99%

Role of 26S proteasome and HRD genes in the degradation of 3-hydroxy-3-methylglutaryl-CoA reductase, an integral endoplasmic reticulum membrane protein.

Hampton

Gardner

Rine

1996

MBoC

528

534

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“…The effect, however, is too small to account for the measured increase in total hepatic protein (Baraona & Lieber, 1982). Moreover, proteins stored in secretory vesicles are subject to lysosomal degradation (Bienkowski, 1983).…”

Section: Introductionmentioning

confidence: 96%

Inhibition of intracellular protein degradation by ethanol in perfused rat liver

Pösö¹,

Surmacz²,

Mortimore³

1987

Biochemical Journal

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Ethanol (50 mM) inhibited proteolysis in the perfused rat liver during stringent amino acid deprivation and also in the presence of normal and 10 times normal concentrations of plasma amino acids. The concentration-response curve of ethanol reached a plateau after 5 mm in both the presence and the absence of normal plasma amino acids, suggesting inhibition by oxidation products of ethanol. Intracellular glutamine, tyrosine and proline increased in concentration with ethanol, but the increases were too small to explain the observed inhibition of proteolysis. The uptake of 1251-asialofetuin was slightly decreased and the output of ammonia increased in the presence of ethanol. These, together with a significant suppression of basal proteolysis in the presence of amino acids, suggest that lysosomal function was directly affected. Electron-microscopic examination of lysosomal components showed that the aggregate volume of autophagosomes (initial vacuoles) were significantly smaller in livers perfused with ethanol than in controls. However, the equivalent volume of autolysosomes (degradative vacuoles) was the same in both groups. According to these results, ethanol inhibits protein degradation in the liver by two discrete mechanisms: one decreasing the formation of autophagic vacuoles and the other involving lysosomotropic inhibition, possibly via ammonia.

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“…The general agreement would be that, gingival hyperplasia is seen in patients under pheytoin is mainly the consequence of the increase in amount of connective tissue rather than a marked epithelial hyperplasia [6][7]. Literatures also suggest that major change in phenytoin gingival hyperplasia is due to the increase number of collagen but it still remains unclear if its caused by the increased number of fibroblast or elevated cellular activity [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%