Highly divergent amino termini of the homologous human ALR and yeast scERV1 gene products define species specific differences in cellular localization

Hofhaus, Götz; Stein, Georg; Polimeno, Lorenzo; Francavilla, A.; Lisowsky, Thomas

doi:10.1016/s0171-9335(99)80069-7

Cited by 42 publications

(53 citation statements)

References 35 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: 85%

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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: 85%

“…The C-terminus of mammalian ALR is 40% identical with ERV1P (essential for respiration and vegetative growth 1 protein) [16], product of the Saccharomyces cerevisiae gene ERV1 [17,18]. ERV1p and ALR are flavin-containing sulfhydryl oxidases localized in the mitochondrial intermembrane space [19][20][21].…”

Section: Introductionmentioning

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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“…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)(6)(7)(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).…”

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%

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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“…HSS has also been referred to as augmenter of liver regeneration (ALR) or hepatopoietin, as it is able to enhance the growth of hepatocytes or hepatoma cells when combined with other hepatotrophic mitogens, such as epidermal growth factor (EGF) and transforming growth factor (TGF)-a, regardless of the animal species. Although HSS is synthesized in the liver parenchymal cells (He et al, 1993), it has multiple-tissue expression (Giorda et al, 1996), various subcellular localizations (Hofhaus et al, 1999), and diverse functions (Pawlowski and Jura, 2006). HSS exists in either a longer (with 205 amino acids) or a shorter form (with only 125 amino acids).…”

Section: Introductionmentioning

confidence: 99%

Adenoviral Gene Transfer of Hepatic Stimulator Substance Confers Resistance Against Hepatic Ischemia–Reperfusion Injury by Improving Mitochondrial Function

Jiang

2013

Human Gene Therapy

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Hepatic stimulator substance (HSS) has been suggested to protect liver cells from various toxins. However, the precise role of HSS in hepatic ischemia-reperfusion (I/R) injury remains unknown. This study aims to elucidate whether overexpression of HSS could attenuate hepatic ischemia-reperfusion injury and its possible mechanisms. Both in vivo hepatic I/R injury in mice and in vitro hypoxia-reoxygenation (H/R) in a cell model were used to evaluate the effect of HSS protection after adenoviral gene transfer. Moreover, a possible mitochondrial mechanism of HSS protection was investigated. Efficient transfer of the HSS gene into liver inhibited hepatic I/R injury in mice, as evidenced by improvement in liver function tests, the preservation of hepatic morphology, and a reduction in hepatocyte apoptosis. HSS overexpression also inhibited H/R-induced cell death, as detected by cell viability and cell apoptosis assays. The underlying mechanism of this hepatic protection might involve the attenuation of mitochondrial dysfunction and mitochondrial-dependent cell apoptosis, as shown by the good preservation of mitochondrial ultrastructure, mitochondrial membrane potential, and the inhibition of cytochrome c leakage and caspase activity. Moreover, the suppression of H/R-induced mitochondrial ROS production and the maintenance of mitochondrial respiratory chain complex activities may participate in this mechanism. This new function of HSS expands the possibility of its application for the prevention of I/R injury, such as hepatic resection and liver transplantation in clinical practice.

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Highly divergent amino termini of the homologous human ALR and yeast scERV1 gene products define species specific differences in cellular localization

Cited by 42 publications

References 35 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

Adenoviral Gene Transfer of Hepatic Stimulator Substance Confers Resistance Against Hepatic Ischemia–Reperfusion Injury by Improving Mitochondrial Function

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