Tunicamycin — An inhibitor of yeast glycoprotein synthesis

Kuo, S.‐C.; Lampen, J. O.

doi:10.1016/0006-291x(74)90925-5

Cited by 285 publications

(109 citation statements)

References 12 publications

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“…The antibiotic TM inhibits the glycosylation of proteins by blocking the formation of N-acetylglucosaminyldiphosphorylpolyisoprenol, essential for the glycosylation of asparagine residues of proteins (6,18,19,(37)(38)(39). Previous studies have shown that these carbohydrate moieties are not required for the synthesis, intracellular processing, secretion, or biological activity of a variety of glycoproteins (7-9, 11, 14-17, 20, 21, 24).…”

Section: Discussionmentioning

confidence: 99%

“…Treatment of cells with TM results in the synthesis of glycoproteins deficient in asparagine-linked oligosaccharides (6,18,19). TM has been utilized to study the contribution of the oligosaccharide components to the posttranslational processing (16,17), intracellular transport (9,16,17), secretion (7,9,13,(15)(16)(17)(20)(21)(22)(23), and functional properties (9,24) of specific glycoproteins.…”

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confidence: 99%

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Carbohydrate requirement for expression and stability of acetylcholine receptor on the surface of embryonic muscle cells in culture.

Prives¹,

Olden²

1980

Proc. Natl. Acad. Sci. U.S.A.

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We have investigated the significance of protein glycosylation for metabolism of acetylcholine receptors (AcChoR) in primary cultures of embryonic chicken muscle cells. Tunicamycin, a specific inhibitor of the glycosylation of asparagine residues on glycoproteins, decreased AcChoR accumulation and accelerated its degradation. In contrast, there was no evidence that tunicamycin treatment affected AcChoR biosynthesis, intracellular transport, or incorporation into surface membranes. Leupeptin, an inhibitor of intracellular proteases, markedly increased accumulation of AcChoR on the external surface of muscle cells treated with tunicamycin. Our findings indicate that impairment of protein glycosylation prevents accumulation of AcChoR by increasing its susceptibility to degradation by cellular proteases.is strongly impaired by TM treatment. However, the proteolytic degradation of underglycosylated AcChoR is substantially increased under these conditions, resulting in marked diminution of AcChoR accumulation. The protease inhibitor leupeptin substantially reverses the decrease in AcChoR in TM-treated cultures, suggesting that glycosylation stabilizes AcChoR against proteolytic degradation. The possibility that the carbohydrate on AcChoR may function in regulating its stability is supported by our findings that: (i) impaired protein glycosylation results in accelerated degradation of AcChoR, and (ii) concanavalin A (Con A), a ligand of AcChoR (2,3), increases AcChoR stability in control cultures but not in TM-treated cells.The acetylcholine receptor (AcChoR) of skeletal muscle cells is an integral membrane glycoprotein that is uniquely well characterized both pharmacologically and biochemically (for recent reviews see refs. 1-3). Thus AcChoR may serve as a model for detailed study of the function of the carbohydrate components of glycoproteins in the regulation of well-defined plasma membrane properties. AcChoR is of particular interest because its synthesis, distribution on the muscle cell surface, and degradation are tightly regulated during differentiation and upon innervation (3). The striking effects induced under neuronal influence include the disappearance of AcChoR from extrasynaptic regions of the muscle cell surface and a marked decrease in the degradation rate of synaptic AcChoR (3). The regulation of AcChoR metabolism has recently been intensively studied in cell cultures of differentiating skeletal muscle (3, 4) using 25I-labeled a-bungarotoxin ('25I-a-Bgt), a specific ligand that binds to AcChoR with high specificity and low reversibility (5).The function of carbohydrate components of glycoproteins can be conveniently studied in cultured cells by the use of tunicamycin (TM), an antibiotic that specifically inhibits protein glycosylation (6-17). Treatment of cells with TM results in the synthesis of glycoproteins deficient in asparagine-linked oligosaccharides (6,18,19). TM has been utilized to study the contribution of the oligosaccharide components to the posttranslational processing (16, 17), i...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Carbohydrate requirement for expression and stability of acetylcholine receptor on the surface of embryonic muscle cells in culture.

Prives¹,

Olden²

1980

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, since tunicamycin inhibits the formation of N-acetyl glucosaminyl pyrrophosphoryl dolichol, the synthesis of diacetylchitobiose which forms the initial building block of the core oligosaccharide is prevented (17). Tunicamycin, when applied to regenerating Euglena, totally inhibits ['"C]xylose incorporation into both flagellar glycoproteins and into presumptive oligosaccharide lipids.…”

Section: Possible Biochemical Pathways For the Synthesis Of Flagellarmentioning

confidence: 99%

Synthesis and mobilization of flagellar glycoproteins during regeneration in Euglena.

Geetha-Habib¹,

Bouck²

1982

The Journal of Cell Biology

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Flagellar glycoprotein synthesis and mobilization of flagellar glycoprotein pools have been followed during flagellar regeneration in Euglena . The glycosylation inhibitor tunicamycin has little effect on either regeneration kinetics or the complement of flagellar peptides as seen in SDS acrylamide gels, but tunicamycin totally inhibits incorporation of exogenously supplied [ t4 C]xylose into flagellar glycoproteins . Moreover, deflagellated cells pulsed with tunicamycin for 30 min or more, regenerated for 180 min, and then redeflagellated are completely or partially inhibited from undergoing a second regeneration even when tunicamycin is no longer present. These facts are interpreted as indicating that Euglena retains sufficient glycoprotein pool for one complete flagellar assembly . Some of this pool is present on the cell surface since [' 25 1]-labeled surface peptides can be chased into the regenerating flagellum . Glycosylation may also be taking place in the flagellum directly because [ 14 C] xylose has been found in three flagellar fractions: glycoprotein and two others, which are lipophilic and have properties similar to those described for lipid-carrier glycoprotein intermediates in other systems. Pulse-chase experiments also suggest a precursor-product relationship between the presumptive lipid carriers and flagellar glycoproteins . From these results a model is postulated in which Euglena is visualized as retaining sufficient pool of glycoprotein for one complete flagellar regeneration, but the pool is normally supplemented by active xylosylation in situ during regeneration .During regeneration the flagellar membrane and its associated surface glycoproteins such as mastigonemes and scales are assembled in a relatively short period after flagellar withdrawal or excision . As with the well-studied flagellar axonemes, the regenerating flagellum can also be used to identify precursors and the mobilization of the components of the flagellar surface, and to determine how much, if any, control they exert on regeneration . In Euglena such analyses are facilitated by the distinctive properties of the flagellar surface when compared with those of the remainder of the cell . The predominance of xylose as the major saccharide of the abundant flagellar glycoproteins is particularly striking since other regions of the cell have no detectable quantities of this sugar (8). This unique biochemical marker suggested that flagellar glycoproteins might be selectively identified and their assembly and insertion followed in appropriate regeneration experiments . Evidence is presented in this report that exogenously added [t'CJxylose is incorporated into flagellar glycolipids and glycoproteins. This has permitted the tentative identification of putative lipid intermediates in the flagellum, of substantial glycoprotein 432 M.

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“…Early investigations have demonstrated that this antibiotic was able to inhibit the synthesis of N‐glycoproteins in yeast and bacteria (Kuo and Lampen 1974; Bettinger and Young 1975) as well as in animals and plants (Fig. 2) (Takatsuki and Tamura 1971; Tkacz and Lampen 1975; Ericson et al.…”

Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

194

161

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Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.

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Tunicamycin — An inhibitor of yeast glycoprotein synthesis

Cited by 285 publications

References 12 publications

Carbohydrate requirement for expression and stability of acetylcholine receptor on the surface of embryonic muscle cells in culture.

Carbohydrate requirement for expression and stability of acetylcholine receptor on the surface of embryonic muscle cells in culture.

Synthesis and mobilization of flagellar glycoproteins during regeneration in Euglena.

Role of endoplasmic reticulum stress in drug‐induced toxicity

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