Endoplasmic Reticulum Oxidoreductin 1-Lβ (ERO1-Lβ), a Human Gene Induced in the Course of the Unfolded Protein Response

Pagani, Massimiliano; Fabbri, Marco; Benedetti, Cristina; Fassio, Anna; Pilati, S.; Bulleid, Neil J.; Cabibbo, Andrea; Sitia, Roberto

doi:10.1074/jbc.m003061200

Cited by 247 publications

(261 citation statements)

References 35 publications

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“…Strikingly, two of the five remaining genes, Ero1lb and Nnat, encode ER resident proteins implicated in ER stress responses whose differential expression we had already observed in AdshPdx1-infected Min6 cells (Fig. 5A) (26,28). After confirming these results using an independent approach to silence Pdx1 (Fig.…”

Section: Uprsupporting

confidence: 72%

Pdx1 ( MODY4 ) regulates pancreatic beta cell susceptibility to ER stress

Sachdeva

Claiborn

Khoo

et al. 2009

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

211

174

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Type 2 diabetes mellitus (T2DM) results from pancreatic ␤ cell failure in the setting of insulin resistance. Heterozygous mutations in the gene encoding the ␤ cell transcription factor pancreatic duodenal homeobox 1 (Pdx1) are associated with both T2DM and maturity onset diabetes of the young (MODY4), and low levels of Pdx1 accompany ␤ cell dysfunction in experimental models of glucotoxicity and diabetes. Here, we find that Pdx1 is required for compensatory ␤ cell mass expansion in response to diet-induced insulin resistance through its roles in promoting ␤ cell survival and compensatory hypertrophy. Pdx1-deficient ␤ cells show evidence of endoplasmic reticulum (ER) stress both in the complex metabolic milieu of high-fat feeding as well as in the setting of acutely reduced Pdx1 expression in the Min6 mouse insulinoma cell line. Further, Pdx1 deficiency enhances ␤ cell susceptibility to ER stressassociated apoptosis. The results of high throughput expression microarray and chromatin occupancy analyses reveal that Pdx1 regulates a broad array of genes involved in diverse functions of the ER, including proper disulfide bond formation, protein folding, and the unfolded protein response. These findings suggest that Pdx1 deficiency leads to a failure of ␤ cell compensation for insulin resistance at least in part by impairing critical functions of the ER.chromatin occupancy ͉ diabetes ͉ gene regulation ͉ islet compensation

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Section: Uprsupporting

confidence: 72%

Pdx1 ( MODY4 ) regulates pancreatic beta cell susceptibility to ER stress

Sachdeva

Claiborn

Khoo

et al. 2009

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

211

174

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“…A prerequisite for the catalytic activity of PDI is the presence of proteins of the Ero1 family within the ER Mezghrani et al 2001;Sevier and Kaiser 2008). These oxidoreductases, represented by Ero1α and Ero1β in human cells, mediate the re-oxidation of PDI after its enzymatic reaction by transferring oxidative equivalents using their CXXCXXC active sites (Benham et al 2000;Pagani et al 2000). The oxidative power of Ero1 proteins originate from their flavin adenine dinucleotide (FAD) prosthetic group that transfers electrons from cysteines to molecular oxygen (Wang et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Ero1α requires oxidizing and normoxic conditions to localize to the mitochondria-associated membrane (MAM)

Gilady

Bui

Lynes

et al. 2010

Cell Stress and Chaperones

159

115

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Protein secretion from the endoplasmic reticulum (ER) requires the enzymatic activity of chaperones and oxidoreductases that fold polypeptides and form disulfide bonds within newly synthesized proteins. The best-characterized ER redox relay depends on the transfer of oxidizing equivalents from molecular oxygen through ER oxidoreductin 1 (Ero1) and protein disulfide isomerase to nascent polypeptides. The formation of disulfide bonds is, however, not the sole function of ER oxidoreductases, which are also important regulators of ER calcium homeostasis. Given the role of human Ero1α in the regulation of the calcium release by inositol 1,4,5-trisphosphate receptors during the onset of apoptosis, we hypothesized that Ero1α may have a redox-sensitive localization to specific domains of the ER. Our results show that within the ER, Ero1α is almost exclusively found on the mitochondria-associated membrane (MAM). The localization of Ero1α on the MAM is dependent on oxidizing conditions within the ER. Chemical reduction of the ER environment, but not ER stress in general leads to release of Ero1α from the MAM. In addition, the correct localization of Ero1α to the MAM also requires normoxic conditions, but not ongoing oxidative phosphorylation.

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“…They include: yeast ERV1 (essential for respiration and vegetative growth) (1) and its mammalian counterpart augmenter of liver regeneration, ALR, (2-4); yeast Erv2p (5-7); an Arabidopsis homolog of these proteins (8,9); yeast and its vertebrate orthologs Ero1α and Ero1β (15,16); and finally larger multidomain sulfhydryl oxidases, containing an ERV/ALR module fused to a redox active thioredoxin domain, that are found principally in multicellular organisms (17)(18)(19)(20) The ERV/ALR proteins and their larger cousins in the QSOX family all contain a diminutive helix-rich flavin binding domain first reported for yeast Erv2p by Fass and coworkers (6) and for rat ALR by Rose and colleagues (4). Subunit A of the Erv2p homodimer is shown in the foreground of Figure 1.…”

Section: Introductionmentioning

confidence: 99%

Erv2p: Characterization of the Redox Behavior of a Yeast Sulfhydryl Oxidase

2007

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The FAD prosthetic group of the ERV/ALR family of sulfhydryl oxidases is housed at the mouth of a 4-helix bundle and communicates with a pair of juxtaposed cysteine residues that form the proximal redox active disulfide. Most of these enzymes have one or more additional distal disulfide redox centers that facilitate the transfer of reducing equivalents from the dithiol substrates of these oxidases to the isoalloxazine ring where the reaction with molecular oxygen occurs. The present study examines yeast Erv2p and compares the redox behavior of this ER luminal protein with the augmenter of liver regeneration, a sulfhydryl oxidase of the mitochondrial intermembrane space, and a larger protein containing the ERV/ALR domain, quiescin-sulfhydryl oxidase (QSOX). Dithionite and photochemical reductions of Erv2p show full reduction of the flavin cofactor after the addition of 4-electrons with a mid-point potential of -200 mV at pH 7.5. A charge-transfer complex between a proximal thiolate and the oxidized flavin is not observed in Erv2p consistent with a distribution of reducing equivalents over the flavin and distal disulfide redox centers. Upon coordination with Zn 2+ , full reduction of Erv2p requires 6-electrons. Zn 2+ also strongly inhibits Erv2p when assayed using tris(2-carboxyethyl)phosphine (TCEP) as the reducing substrate of the oxidase. In contrast to QSOX, Erv2p shows a comparatively low turnover with a range of small thiol substrates, with reduced Escherichia coli thioredoxin and with unfolded proteins. Rapid reaction studies confirm that reduction of the flavin center of Erv2p is rate-limiting during turnover with molecular oxygen. This comparison of the redox properties between members of the ERV/ALR family of sulfhydryl oxidases provides insights into their likely roles in oxidative protein folding.Over the last decade a number of eukaryotic flavin-dependent sulfhydryl oxidases have been described that catalyze the net generation of disulfide bonds:They include: yeast ERV1 (essential for respiration and vegetative growth) (1) and its mammalian counterpart augmenter of liver regeneration, ALR, (2-4); yeast Erv2p (5-7); an Arabidopsis homolog of these proteins (8,9); yeast and its vertebrate orthologs Ero1α and Ero1β (15,16); and finally larger multidomain sulfhydryl oxidases, containing an ERV/ALR module fused to a redox active thioredoxin domain, that are found principally in multicellular organisms (17)(18)(19)(20) The ERV/ALR proteins and their larger cousins in the QSOX family all contain a diminutive helix-rich flavin binding domain first reported for yeast Erv2p by Fass and coworkers (6) and for rat ALR by Rose and colleagues (4). Subunit A of the Erv2p homodimer is shown in the foreground of Figure 1. The isoalloxazine ring is inserted at the end of a bundle of four helices in the A subunit with its C2/N3 region exposed to solvent (6). The proximal disulfide C121-124 is placed so that the sulfur of C124 is adjacent (3.4 Å) to the C 4a position of the flavin. This locus is consistent with i...

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Endoplasmic Reticulum Oxidoreductin 1-Lβ (ERO1-Lβ), a Human Gene Induced in the Course of the Unfolded Protein Response

Cited by 247 publications

References 35 publications

Pdx1 ( MODY4 ) regulates pancreatic beta cell susceptibility to ER stress

Pdx1 ( MODY4 ) regulates pancreatic beta cell susceptibility to ER stress

Ero1α requires oxidizing and normoxic conditions to localize to the mitochondria-associated membrane (MAM)

Erv2p: Characterization of the Redox Behavior of a Yeast Sulfhydryl Oxidase

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