Endoplasmic Reticulum Oxidoreductin-1α (Ero1α) Improves Folding and Secretion of Mutant Proinsulin and Limits Mutant Proinsulin-induced Endoplasmic Reticulum Stress

Wright, Jordan; Birk, Julia; Haataja, Leena; Liu, Ming; Ramming, Thomas; Weiss, Michael A.; Appenzeller-Herzog, Christian; Arvan, Peter

doi:10.1074/jbc.m113.510065

Cited by 40 publications

(36 citation statements)

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“…Increased expression of ER oxidoreductin-1 (Ero1), which helps to catalyze disulfide bond formation in the ER (37), has been found to promote significant escape/rescue of the wild-type proinsulin that is coexpressed with MIDY mutants in the ER (12). Curiously, we also discovered that increased Ero1 expression could directly rescue ER export of a very small fraction of some of the MIDY mutants themselves (14), and this effect has not been adequately explained. To test whether an improvement of proinsulin oxidative folding might account for a small degree of secretory rescue achievable with MIDY mutants, we briefly exposed cells to diamide (1 mmol/L), followed immediately thereafter by diamide washout.…”

Section: Resultsmentioning

confidence: 99%

“…To the best of our knowledge, all MIDY mutations perturb the native disulfide pairing of proinsulin (9,10). The process of proinsulin disulfide bond formation in vivo is complicated by the rapid time scale (<1 min) for proinsulin translation/translocation into the ER lumen (11), the timing of preproinsulin signal peptide cleavage (12), the regulation of the ER lumenal redox environment (13,14), and activity of ER oxidoreductases (15). It is recognized that all three disulfide bonds of insulin, the two “interchain” disulfide bonds called Cys(B7)-Cys(A7) and Cys(B19)-Cys(A20) as well as the intra-A chain disulfide Cys(A6)-Cys(A11)—all of which form within proinsulin—must be intact for optimal insulin bioactivity on the insulin receptor (16).…”

Section: Introductionmentioning

confidence: 99%

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Disulfide Mispairing During Proinsulin Folding in the Endoplasmic Reticulum

et al. 2016

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Proinsulin folding within the endoplasmic reticulum (ER) remains incompletely understood, but it is clear that in mutant INS gene–induced diabetes of youth (MIDY), progression of the (three) native disulfide bonds of proinsulin becomes derailed, causing insulin deficiency, β-cell ER stress, and onset of diabetes. Herein, we have undertaken a molecular dissection of proinsulin disulfide bond formation, using bioengineered proinsulins that can form only two (or even only one) of the native proinsulin disulfide bonds. In the absence of preexisting proinsulin disulfide pairing, Cys(B19)-Cys(A20) (a major determinant of ER stress response activation and proinsulin stability) preferentially initiates B-A chain disulfide bond formation, whereas Cys(B7)-Cys(A7) can initiate only under oxidizing conditions beyond that existing within the ER of β-cells. Interestingly, formation of these two “interchain” disulfide bonds demonstrates cooperativity, and together, they are sufficient to confer intracellular transport competence to proinsulin. The three most common proinsulin disulfide mispairings in the ER appear to involve Cys(A11)-Cys(A20), Cys(A7)-Cys(A20), and Cys(B19)-Cys(A11), each disrupting the critical Cys(B19)-Cys(A20) pairing. MIDY mutations inhibit Cys(B19)-Cys(A20) formation, but treatment to force oxidation of this disulfide bond improves folding and results in a small but detectable increase of proinsulin export. These data suggest possible therapeutic avenues to ameliorate ER stress and diabetes.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Disulfide Mispairing During Proinsulin Folding in the Endoplasmic Reticulum

et al. 2016

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“…On a different note, an emerging therapeutic concept is to kill solid tumors by redox attack, which is most prominently illustrated by the preclinical success of photodynamic therapies (Garg and Agostinis, 2014), as well as by the use of PDI inhibitors (Higa et al, 2014;Xu et al, 2014). Finally, defective insulin secretion and ER stress that is caused by folding-impaired genetic variants of proinsulin can be rescued by expression of hyperactive Ero1 (Wright et al, 2013), although increasing Ero1 activity in healthy b-cells predisposes them to developing ER stress and diabetes (Awazawa et al, 2014). Thus, targeted ER hyper-oxidation might be a viable therapeutic strategy in a subset of diabetic syndromes.…”

Section: Discussionmentioning

confidence: 99%

Redox controls UPR to control redox

Eletto

Chevet

Argon

et al. 2014

Journal of Cell Science

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154

137

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In many physiological contexts, intracellular reduction-oxidation (redox) conditions and the unfolded protein response (UPR) are important for the control of cell life and death decisions. UPR is triggered by the disruption of endoplasmic reticulum (ER) homeostasis, also known as ER stress. Depending on the duration and severity of the disruption, this leads to cell adaptation or demise. In this Commentary, we review reductive and oxidative activation mechanisms of the UPR, which include direct interactions of dedicated protein disulfide isomerases with ER stress sensors, protein S-nitrosylation and ER Ca 2+ efflux that is promoted by reactive oxygen species. Furthermore, we discuss how cellular oxidant and antioxidant capacities are extensively remodeled downstream of UPR signals. Aside from activation of NADPH oxidases, mitogen-activated protein kinases and transcriptional antioxidant responses, such remodeling prominently relies on ER-mitochondrial crosstalk. Specific redox cues therefore operate both as triggers and effectors of ER stress, thus enabling amplification loops. We propose that redox-based amplification loops critically contribute to the switch from adaptive to fatal UPR.

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“…Mammals have two genes which encode proteins homologous to ERO1a, known as ERO1a and ERO1b [16]. Wright and colleagues [17] have found that ERO1a limits mutant proinsulin-induced ER stress. Modest inhibition of ERO1a promotes signaling in the UPR and precondition cells against severe ER stress [18].…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic reticulum oxidoreductin 1α mediates hepatic endoplasmic reticulum stress in homocysteine-induced atherosclerosis

Yang¹,

Xu²,

Hao³

et al. 2014

ABBS

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Endoplasmic reticulum (ER) stress is emerging as an important modulator of different pathological process and as a mechanism contributing to homocysteine (Hcy)-induced hepar injury. However, the molecular event that Hcyinduced ER stress in the hepar under the atherosclerosis background is currently unknown. Endoplasmic reticulum oxidoreductin 1a (ERO1a) plays a crucial role in maintaining ER stress function. In this study, we determined the expression of ERO1a in the hepar in hyperhomocysteinemia and the effect of ERO1a in hepacytes ER stress in the presence of Hcy. HHcy model was established by feeding the methionine diet in apolipoprotein-E-deficient (ApoE-/-) mice, and the hepatocytes were incubated with folate and different concentrations of Hcy. Our results showed that Hcy triggered ER stress characterized by an increased contents of glucoseregulated protein 78 (GRP78), protein kinase RNA-like ER kinase (PERK), activating transcription factor (ATF) 6 and X-box binding protein-1 (XBP-1). The ERO1a expressions in HHcy mice and Hcy-treated hepatocytes were decreased compared with those in ApoE-/-group and control hepacytes (P < 0.05), respectively. Knocking-down the expression of ERO1a with small-interfering RNA significantly augmented Hcy-induced ER stress. Meanwhile, the expressions of ER stress-related factor including GRP78, PERK, ATF6 and XBP-1, were significantly decreased when the ERO1a gene was over-expressed in hepacytes. Our results suggested that ERO1a may be involved in Hcy-induced hepar ER stress, and the inhibition of ERO1a expression can accelerate this process.

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Endoplasmic Reticulum Oxidoreductin-1α (Ero1α) Improves Folding and Secretion of Mutant Proinsulin and Limits Mutant Proinsulin-induced Endoplasmic Reticulum Stress

Cited by 40 publications

References 46 publications

Disulfide Mispairing During Proinsulin Folding in the Endoplasmic Reticulum

Disulfide Mispairing During Proinsulin Folding in the Endoplasmic Reticulum

Redox controls UPR to control redox

Endoplasmic reticulum oxidoreductin 1α mediates hepatic endoplasmic reticulum stress in homocysteine-induced atherosclerosis

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Endoplasmic Reticulum Oxidoreductin-1α (Ero1α) Improves Folding and Secretion of Mutant Proinsulin and Limits Mutant Proinsulin-induced Endoplasmic Reticulum Stress

Cited by 40 publications

References 46 publications

Disulfide Mispairing During Proinsulin Folding in the Endoplasmic Reticulum

Disulfide Mispairing During Proinsulin Folding in the Endoplasmic Reticulum

Redox controls UPR to control redox

Endoplasmic reticulum oxidoreductin 1&alpha; mediates hepatic endoplasmic reticulum stress in homocysteine-induced atherosclerosis

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Endoplasmic reticulum oxidoreductin 1α mediates hepatic endoplasmic reticulum stress in homocysteine-induced atherosclerosis