A mutant for the yeastscERV1 gene displays a new defect in mitochondrial morphology and distribution

Becher, Dietmar; Kricke, Jörn; Stein, Georg; Lisowsky, Thomas

doi:10.1002/(sici)1097-0061(19990915)15:12<1171::aid-yea443>3.0.co;2-t

Cited by 58 publications

(48 citation statements)

References 42 publications

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“…Both an apoptosis-dependent increase in ATP consumption and a separate decrease in ATP synthesis may contribute to the lethal ATP depletion, global loss of cellular integrity, and necrosis [44] of ALR-AS-treated hepatocytes. In support of this supposition, ERV1P is shown to be essential for the biogenesis of mitochondria [17,22,32], normal mitochondrial morphology and stable maintenance of mitochondria in S. cerevisiae [16,45]. Disruption of the ERV-1 gene results in complete loss of mitochondrial genome and death of the yeast following a few replications [22].…”

Section: Discussionmentioning

confidence: 86%

“…Although ALR and ERV-1 are essential for the survival of hepatocytes and S. cerevisiae, respectively, a major difference is that ALR is abundantly expressed in hepatocytes [12], but the expression of ERV-1 is very low in the yeast [45]. Despite the low level of ERV-1 expression, null mutation in the gene in the haploid yeast strain stopped their replication after 3-4 days [17]; it was suggested that this effect was due to high in vivo stability of the ERV-1 mRNA and protein.…”

Section: Discussionmentioning

confidence: 99%

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Augmenter of liver regeneration: An important intracellular survival factor for hepatocytes

Thirunavukkarasu

Wang

Harvey

et al. 2008

Journal of Hepatology

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Background/Aims-Augmenter of liver regeneration (ALR), a protein synthesized and stored in hepatocytes, is associated with mitochondria, and possesses sulfhydryl oxidase and cytochrome c reductase activities. We sought to determine the effects of ALR depletion in hepatocytes by antisense oligonucleotide transfection.Methods-Rat hepatocytes in primary culture were transfected with antisense oligonucleotide for ALR mRNA (ALR-AS) or scrambled oligonucleotide. Various analyses were performed at times up to 24 h after transfection.Results-Treatment with ALR-AS caused a decrease in ALR mRNA, cellular depletion of ALR protein primarily from mitochondria, and decreased viability. Flow cytometric analysis of ALR-AStransfected hepatocytes stained with annexin-V cy3 and 7-aminoactinomycin D revealed apoptosis as the predominant cause of death up to 6 h; incubation beyond this time resulted in necrosis in addition to apoptosis. ALR-AS-transfection caused release of mitochondrial cytochrome c, activation of caspase-3, profound reduction in the ATP content, and cellular release of LDH. Inhibition of caspase-3 inhibited the early phase of ALR-AS-induced death but not the late phase that included ALR and LDH release.Conclusions-These results suggest that ALR is critically important for the survival of hepatocytes by its association with mitochondria and regulation of ATP synthesis. KeywordsAugmenter of liver regeneration; Antisense; Hepatocytes; Apoptosis; Necrosis ☆ The authors who have taken part in the research of this paper declared that they do not have a relationship with the manufacturers of the materials involved either in the past or present and they did not receive funding from the manufacturers to carry out their research.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Augmenter of liver regeneration: An important intracellular survival factor for hepatocytes

Thirunavukkarasu

Wang

Harvey

et al. 2008

Journal of Hepatology

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“…This notion is consistent with the fact that glutathione and dithiothreitol are not used as substrates by both proteins. 2 Both yeast proteins form dimers in vivo that are stable in nonreducing SDS gels, arguing for covalent disulfide bridges between the monomers. However, current evidence suggests that Erv1p and Erv2p use different strategies for dimer formation.…”

Section: Discussionmentioning

confidence: 99%

“…The encoded protein Erv1p is required for maintenance of intact mitochondria in the cell (2). Recently, Erv1p was demonstrated to function as a sulfhydryl oxidase (3).…”

Section: Erv1mentioning

confidence: 99%

“…Yeast Erv1p was identified mostly inside mitochondria (2,9); the viral E10R protein executes its function in the cytosol (16); and proteins of the quiescin Q6 family are excreted from cells (10,11). The sequence similarities and the conserved YPCXXC motif in the carboxyl-terminal domain indicate that Erv2p is a novel member of the Erv1p/Alrp protein family.…”

Section: Erv1mentioning

confidence: 99%

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Yeast Erv2p Is the First Microsomal FAD-linked Sulfhydryl Oxidase of the Erv1p/Alrp Protein Family

Gerber

Mühlenhoff

Hofhaus

et al. 2001

Journal of Biological Chemistry

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Saccharomyces cerevisiae Erv2p was identified previously as a distant homologue of Erv1p, an essential mitochondrial protein exhibiting sulfhydryl oxidase activity. Expression of the ERV2 (essential for respiration and vegetative growth 2) gene from a high-copy plasmid cannot substitute for the lack of ERV1, suggesting that the two proteins perform nonredundant functions. Here, we show that the deletion of the ERV2 gene or the depletion of Erv2p by regulated gene expression is not associated with any detectable growth defects. Erv2p is located in the microsomal fraction, distinguishing it from the mitochondrial Erv1p. Despite their distinct subcellular localization, the two proteins exhibit functional similarities. Both form dimers in vivo and in vitro, contain a conserved YPCXXC motif in their carboxylterminal part, bind flavin adenine dinucleotide (FAD) as a cofactor, and catalyze the formation of disulfide bonds in protein substrates. The catalytic activity, the ability to form dimers, and the binding of FAD are associated with the carboxyl-terminal domain of the protein. Our findings identify Erv2p as the first microsomal member of the Erv1p/Alrp protein family of FAD-linked sulfhydryl oxidases. We propose that Erv2p functions in the generation of microsomal disulfide bonds acting in parallel with Ero1p, the essential, FAD-dependent oxidase of protein disulfide isomerase. ERV11 is an essential gene of the yeast Saccharomyces cerevisiae (1). The encoded protein Erv1p is required for maintenance of intact mitochondria in the cell (2). Recently, Erv1p was demonstrated to function as a sulfhydryl oxidase (3). This enzymatic activity is associated with the carboxyl-terminal part that harbors a YPCXXC motif and noncovalently bound FAD. Yeast contains a distant homologue of Erv1p termed Erv2p (4). The sequence similarities are restricted to the carboxyl-terminal part of the proteins, including a highly conserved YPCXXC motif. The functions of Erv1p and Erv2p seem to be nonredundant, because overexpression of Erv2p complemented neither a conditional mutant of ERV1 nor a deletion mutant of this gene (4).Recently, a few other proteins have been identified containing a domain with homology to the carboxyl-terminal portion of Erv1p. This part is the hallmark of the new Erv1p/Alrp protein family and comprises 80 -100 amino acid residues. It contains a CXXC motif that is responsible for disulfide bond formation activity. In mammals, members of this protein family have been characterized as important growth factors. The human ALR (augmenter of liver regeneration) gene encodes a hepatotrophic growth factor (5-8), the carboxyl-terminal part of which can functionally replace the corresponding yeast Erv1p sulfhydryl oxidase domain (8, 9). The human and chicken Q6 inhibitors of cell growth have a function in the reversible silencing of the division of fibroblasts and also contain a domain homologous to Erv1p and Alrp (10). The chicken Q6 protein is the enzymatically best-characterized sulfhydryl oxidase of the Erv1p/Alrp protei...

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A mutant for the yeastscERV1 gene displays a new defect in mitochondrial morphology and distribution

Cited by 58 publications

References 42 publications

Augmenter of liver regeneration: An important intracellular survival factor for hepatocytes

Augmenter of liver regeneration: An important intracellular survival factor for hepatocytes

Yeast Erv2p Is the First Microsomal FAD-linked Sulfhydryl Oxidase of the Erv1p/Alrp Protein Family

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