Transit of H2O2 across the endoplasmic reticulum membrane is not sluggish

Appenzeller-Herzog, Christian; Bánhegyi, Gábor; Bogeski, Ivan; Davies, Kelvin J.A.; Delaunay‐Moisan, Agnès; Forman, Henry Jay; Görlach, Agnes; Kietzmann, Thomas; Laurindo, Francisco Rafael Martins; Margittai, Éva; Meyer, Andreas; Riemer, Jan; Rützler, Michael; Simmen, Thomas; Sitia, Roberto; Toledano, Michel B.; Touw, Ivo P.

doi:10.1016/j.freeradbiomed.2016.02.030

Cited by 52 publications

(44 citation statements)

References 57 publications

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“…However, the concentration-dependent reduction of H 2 O 2 by GSH is poised to counteract a build-up of ER H 2 O 2 . Although uncertainty regarding the rate of H 2 O 2 transported across the ER membrane exists [38], we favor a model whereby such transport is comparatively slow [11], which is consistent with the observed delay between the increase in ER and cytosolic H 2 O 2 when glutathione synthesis was inhibited. Sequestration of H 2 O 2 in the lumen of the ER protects the genome from this potentially harmful metabolite and enables the higher concentrations needed for the uncatalyzed reaction to progress at a reasonable pace.…”

Section: Discussionsupporting

confidence: 78%

TriPer, an optical probe tuned to the endoplasmic reticulum tracks changes in luminal H2O2

et al. 2017

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BackgroundThe fate of hydrogen peroxide (H2O2) in the endoplasmic reticulum (ER) has been inferred indirectly from the activity of ER-localized thiol oxidases and peroxiredoxins, in vitro, and the consequences of their genetic manipulation, in vivo. Over the years hints have suggested that glutathione, puzzlingly abundant in the ER lumen, might have a role in reducing the heavy burden of H2O2 produced by the luminal enzymatic machinery for disulfide bond formation. However, limitations in existing organelle-targeted H2O2 probes have rendered them inert in the thiol-oxidizing ER, precluding experimental follow-up of glutathione’s role in ER H2O2 metabolism.ResultsHere we report on the development of TriPer, a vital optical probe sensitive to changes in the concentration of H2O2 in the thiol-oxidizing environment of the ER. Consistent with the hypothesized contribution of oxidative protein folding to H2O2 production, ER-localized TriPer detected an increase in the luminal H2O2 signal upon induction of pro-insulin (a disulfide-bonded protein of pancreatic β-cells), which was attenuated by the ectopic expression of catalase in the ER lumen. Interfering with glutathione production in the cytosol by buthionine sulfoximine (BSO) or enhancing its localized destruction by expression of the glutathione-degrading enzyme ChaC1 in the lumen of the ER further enhanced the luminal H2O2 signal and eroded β-cell viability.ConclusionsA tri-cysteine system with a single peroxidatic thiol enables H2O2 detection in oxidizing milieux such as that of the ER. Tracking ER H2O2 in live pancreatic β-cells points to a role for glutathione in H2O2 turnover.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-017-0367-5) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 78%

TriPer, an optical probe tuned to the endoplasmic reticulum tracks changes in luminal H2O2

et al. 2017

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“…AQP3 was also shown to mediate H 2 O 2 uptake to regulate downstream signaling in tumor necrosis factor-dependent activation of NF-κB [100]. The endoplasmic reticulum membrane is recognized as another important site of modulation of H 2 O 2 traffic by aquaporins, notably by AQP11 [101].…”

Section: What Is the Role Of H2o2 In Redox Signaling And Oxidative Stmentioning

confidence: 99%

Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: Oxidative eustress

2017

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Hydrogen peroxide emerged as major redox metabolite operative in redox sensing, signaling and redox regulation. Generation, transport and capture of H2O2 in biological settings as well as their biological consequences can now be addressed. The present overview focuses on recent progress on metabolic sources and sinks of H2O2 and on the role of H2O2 in redox signaling under physiological conditions (1–10 nM), denoted as oxidative eustress. Higher concentrations lead to adaptive stress responses via master switches such as Nrf2/Keap1 or NF-κB. Supraphysiological concentrations of H2O2 (>100 nM) lead to damage of biomolecules, denoted as oxidative distress. Three questions are addressed: How can H2O2 be assayed in the biological setting? What are the metabolic sources and sinks of H2O2? What is the role of H2O2 in redox signaling and oxidative stress?

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“…Similarly, transmembrane transport of H 2 O 2 is likely not mediated passive diffusion but rather by interactions with aquaporins that mediate H 2 O 2 transmembrane passage. [52, 53]…”

Section: Reaction Of H2o2 With Thiol Proteins: Reaction Kinetics Vmentioning

confidence: 99%

The role of sulfenic acids in cellular redox signaling: Reconciling chemical kinetics and molecular detection strategies

Heppner

Janssen–Heininger

Vliet

2017

Archives of Biochemistry and Biophysics

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The reversible oxidation of protein cysteine residues is well recognized as an important regulatory mechanism in redox-dependent cell signaling. Cysteine oxidation is diverse in nature and involves various post-translational modifications (sulfenic acids, disulfides, etc.) and the specific functional or structural impact of these specific oxidative events is still poorly understood. The proximal product of protein cysteine oxidation by biological reactive oxygen species (ROS) is sulfenic acid (Cys-SOH), and experimental evidence is accruing for the formation of Cys-SOH as intermediate in protein cysteine oxidation in various biological settings. However, the plausibility of protein Cys-SH oxidation by ROS has often been put in question because of slow reaction kinetics compared to more favorable reactions with abundant thiol-based reductants such as peroxiredoxins (Prx) or glutathione (GSH). This commentary aims to address this controversy by highlighting the unique physical properties in cells that may restrict ROS diffusion and allow otherwise less favorable cysteine oxidation of proteins. Some limitations of analytical tools to assess Cys-SOH are also discussed. We conclude that formation of Cys-SOH in biological systems cannot always be predicted based on kinetic analyses in homogenous solution, and may be facilitated by unique structural and physical properties of Cys-containing proteins within e.g. signaling complexes.

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Transit of H2O2 across the endoplasmic reticulum membrane is not sluggish

Cited by 52 publications

References 57 publications

TriPer, an optical probe tuned to the endoplasmic reticulum tracks changes in luminal H2O2

TriPer, an optical probe tuned to the endoplasmic reticulum tracks changes in luminal H2O2

Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: Oxidative eustress

The role of sulfenic acids in cellular redox signaling: Reconciling chemical kinetics and molecular detection strategies

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