Alkyl hydroperoxide reductase 1 protects Saccharomyces cerevisiae against metal ion toxicity and glutathione depletion

Nguyên-nhu, Nhu Tiên; Knoops, Bernard

doi:10.1016/s0378-4274(02)00280-1

Cited by 46 publications

(24 citation statements)

References 29 publications

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“…These enzymes are thought to play a role in oxidative homeostasis, stress response and resistance to heavy metal toxicity (15,41), but a specific role in C. posadasii cannot be confidently deduced based on the functions of homologs in other organisms (16). Recently, a different member of the thiol peroxidase family (TSA1) was shown to be essential for growth at 37°C in the pathogenic fungus Cryptococcus neoformans, and deletion mutants were shown to be reduced in virulence (39).…”

Section: Discussionmentioning

confidence: 99%

Protein Expression Profiling of Coccidioides posadasii by Two-Dimensional Differential In-Gel Electrophoresis and Evaluation of a Newly Recognized Peroxisomal Matrix Protein as a Recombinant Vaccine Candidate

et al. 2006

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Coccidioides posadasii and Coccidioides immitis are dimorphic, soil-dwelling pathogenic ascomycetes endemic to the southwestern United States. Infection can result from inhalation of a very few arthroconidia, but following natural infection, long-lived immunity is the norm. Previous work in the field has shown that spherule-derived vaccines afford more protection than those from mycelia. We have used two-dimensional differential in-gel electrophoresis coupled with nano-high-performance liquid chromatography-tandem mass spectrometry to directly assess both absolute abundance and differential expression of proteins in the spherule and the mycelial phases of C. posadasii with the intent to identify potential vaccine candidates. Peptides derived from 40 protein spots were analyzed and a probable identity was assigned to each. One spherule-abundant protein, identified as Pmp1, showed homology to allergens from Aspergillus fumigatus and other fungi, all of which exhibit similarity to yeast thiol peroxidases. Recombinant Pmp1 was reactive with serum from individuals with both acute and protracted disease, and evoked protection in two murine models of infection with C. posadasii. These results demonstrate the utility of proteomic analysis as a point of discovery for protective antigens for possible inclusion in a vaccine candidate to prevent coccidioidomycosis.

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Section: Discussionmentioning

confidence: 99%

Protein Expression Profiling of Coccidioides posadasii by Two-Dimensional Differential In-Gel Electrophoresis and Evaluation of a Newly Recognized Peroxisomal Matrix Protein as a Recombinant Vaccine Candidate

et al. 2006

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“…Here, we show that Urm1p is attached to Ahp1p (alkyl hydroperoxide reductase), a protein implicated in oxidative-stress protection in yeast (41). Furthermore, we identified a potential role for urmylation in oxidativestress response.…”

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confidence: 81%

Attachment of the Ubiquitin-Related Protein Urm1p to the Antioxidant Protein Ahp1p

2003

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Urm1p is a ubiquitin-related protein that serves as a posttranslational modification of other proteins. Urm1p conjugation has been implicated in the budding process and in nutrient sensing. Here, we have identified the first in vivo target for the urmylation pathway as the antioxidant protein Ahp1p. The attachment of Urm1p to Ahp1p requires the E1 for the urmylation pathway, Uba4p. Loss of the urmylation pathway components results in sensitivity to a thiol-specific oxidant, as does loss of Ahp1p, implying that urmylation has a role in an oxidative-stress response. Moreover, treatment of cells with thiol-specific oxidants affects the abundance of Ahp1p-Urm1p conjugates. These results suggest that the conjugation of Urm1p to Ahp1p could regulate the function of Ahp1p in antioxidant stress response in Saccharomyces cerevisiae.An emerging theme in the regulation of protein function is the covalent attachment of one protein to another. An example of this type of modification is provided by ubiquitin, a 76-residue protein that can be attached to other proteins. In many cases, ubiquitination targets the modified proteins for degradation, but other regulatory effects of ubiquitination are also known. Ubiquitin is the founding member of a family of small modifier proteins present in most eukaryotes and known as ubiquitin-like proteins (Ubls) (20). As in the case of the ubiquitin pathway, the attachment of Ubls to targets requires a series of enzymatic steps that include an E1 (an activating enzyme), an E2 (a conjugating enzyme), and sometimes an E3 (protein ligase). Each Ubl is thought to be attached to other proteins via an isopeptide bond between the C terminus of the modifier and a lysine residue of a target protein (18). In contrast to ubiquitin, some of these Ubls do not appear to promote proteolysis but instead appear to alter the function or localization of the target (26,31,33,36).Most of the Ubls are attached to many targets and consequently are involved in the regulation of many processes. Probably the best-characterized ubiquitin-like pathway involves the attachment of SUMO to a rapidly growing set of targets. These substrates include RanGAP1, a Ran GTPase-activating protein involved in nucleocytoplasmic transport (29, 36); IB␣, an inflammatory-response regulatory protein (10); PML (promyelocytic leukemia protein), whose fusion to the retinoic acid receptor causes acute promyelocytic leukemia (29); and Cdc3p, Cdc11p, and Shs1p, proteins in the yeast Saccharomyces cerevisiae that are components of the septin ring involved in cytokinesis (25).In addition to sumoylation, four other ubiquitin-like pathways have been identified in yeast (11,20). The modifier of one of these protein conjugation systems is Urm1p (12); thus, the pathway is termed urmylation. The function of Urm1p conjugation is only beginning to be understood. The E1 for this pathway is Uba4p (12), but other components of the conjugation pathway, such as an E2 or an E3, have yet to be identified. Although urmylation has been linked to budding and inva...

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“…The ability of exogenous copper to stimulate the formation of free radicals in vivo has been demonstrated experimentally (25), and free radical scavengers have been shown to reduce copper-induced neuronal cell death (63). Additionally, disruption of the yeast thioredoxin peroxidase gene Ahp1 induced extreme sensitivity to organic peroxides, a variety of metal ions, and the glutathione-depleting agent diethyl maleate (47). To further define the role of POS5 in the oxidative stress response, we tested the effects of exogenous copper ions on the growth of wild-type and pos5 cultures.…”

Section: Identification Of Mitochondrial Mutatorsmentioning

confidence: 99%

POS5 Gene of Saccharomyces cerevisiae Encodes a Mitochondrial NADH Kinase Required for Stability of Mitochondrial DNA

et al. 2003

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In a search for nuclear genes that affect mutagenesis of mitochondrial DNA in Saccharomyces cerevisiae, an ATP-NAD (NADH) kinase, encoded by POS5, that functions exclusively in mitochondria was identified. The POS5 gene product was overproduced in Escherichia coli and purified without a mitochondrial targeting sequence. A direct biochemical assay demonstrated that the POS5 gene product utilizes ATP to phosphorylate both NADH and NAD ؉ , with a twofold preference for NADH. Disruption of POS5 increased minus-one frameshift mutations in mitochondrial DNA 50-fold, as measured by the arg8 m reversion assay, with no increase in nuclear mutations. Also, a dramatic increase in petite colony formation and slow growth on glycerol or limited glucose were observed. POS5 was previously described as a gene required for resistance to hydrogen peroxide. Consistent with a role in the mitochondrial response to oxidative stress, a pos5 deletion exhibited a 28-fold increase in oxidative damage to mitochondrial proteins and hypersensitivity to exogenous copper. Furthermore, disruption of POS5 induced mitochondrial biogenesis as a response to mitochondrial dysfunction. Thus, the POS5 NADH kinase is required for mitochondrial DNA stability with a critical role in detoxification of reactive oxygen species. These results predict a role for NADH kinase in human mitochondrial diseases.

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Alkyl hydroperoxide reductase 1 protects Saccharomyces cerevisiae against metal ion toxicity and glutathione depletion

Cited by 46 publications

References 29 publications

Protein Expression Profiling of Coccidioides posadasii by Two-Dimensional Differential In-Gel Electrophoresis and Evaluation of a Newly Recognized Peroxisomal Matrix Protein as a Recombinant Vaccine Candidate

Protein Expression Profiling of Coccidioides posadasii by Two-Dimensional Differential In-Gel Electrophoresis and Evaluation of a Newly Recognized Peroxisomal Matrix Protein as a Recombinant Vaccine Candidate

Attachment of the Ubiquitin-Related Protein Urm1p to the Antioxidant Protein Ahp1p

POS5 Gene of Saccharomyces cerevisiae Encodes a Mitochondrial NADH Kinase Required for Stability of Mitochondrial DNA

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