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Destroy and exploit: catalyzed removal of hydroperoxides from the endoplasmic reticulum.

Ramming T, Appenzeller-Herzog C - Int J Cell Biol (2013)

Bottom Line: Peroxidases are enzymes that reduce hydroperoxide substrates.Different peroxide sources and reducing substrates for ER peroxidases are critically evaluated.Peroxidase-catalyzed detoxification of hydroperoxides coupled to the productive use of disulfides, for instance, in the ER-associated process of oxidative protein folding, appears to emerge as a common theme.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstr. 50, 4056 Basel, Switzerland.

ABSTRACT
Peroxidases are enzymes that reduce hydroperoxide substrates. In many cases, hydroperoxide reduction is coupled to the formation of a disulfide bond, which is transferred onto specific acceptor molecules, the so-called reducing substrates. As such, peroxidases control the spatiotemporal distribution of diffusible second messengers such as hydrogen peroxide (H2O2) and generate new disulfides. Members of two families of peroxidases, peroxiredoxins (Prxs) and glutathione peroxidases (GPxs), reside in different subcellular compartments or are secreted from cells. This review discusses the properties and physiological roles of PrxIV, GPx7, and GPx8 in the endoplasmic reticulum (ER) of higher eukaryotic cells where H2O2 and-possibly-lipid hydroperoxides are regularly produced. Different peroxide sources and reducing substrates for ER peroxidases are critically evaluated. Peroxidase-catalyzed detoxification of hydroperoxides coupled to the productive use of disulfides, for instance, in the ER-associated process of oxidative protein folding, appears to emerge as a common theme. Nonetheless, in vitro and in vivo studies have demonstrated that individual peroxidases serve specific, nonoverlapping roles in ER physiology.

No MeSH data available.


RTK signaling involves NOX-derived H2O2 as second messenger. (a) Binding of ligand (L) to receptor tyrosine kinases (RTK) on the cell surface activates NADPH oxidases (NOX) and leads to the generation of extracellular or, following endocytosis, endosomal superoxide (O2−), which can be dismutated to H2O2  (black filled circles). Upon aquaporin 8 (AQP8)-facilitated diffusion across the plasma/endosomal membrane, H2O2 locally inactivates the intracellular negative regulators phosphotyrosine phosphatases (PTPs) and peroxiredoxins (Prxs), which prolongs RTK signal transduction. This step mostly, but not exclusively (as depicted by an asterisk), involves the endoplasmic reticulum (ER)-associated PTP1B. Spatial restriction of H2O2 is achieved by cytosolic ROS scavengers like Prxs. (b) An ER-centered route of RTK-mediated signal transduction involves NOX4 in the ER membrane and PTP1B. In this context, ER-luminal buildup of H2O2 is controlled by ER-resident PrxIV.
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Related In: Results  -  Collection


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fig1: RTK signaling involves NOX-derived H2O2 as second messenger. (a) Binding of ligand (L) to receptor tyrosine kinases (RTK) on the cell surface activates NADPH oxidases (NOX) and leads to the generation of extracellular or, following endocytosis, endosomal superoxide (O2−), which can be dismutated to H2O2  (black filled circles). Upon aquaporin 8 (AQP8)-facilitated diffusion across the plasma/endosomal membrane, H2O2 locally inactivates the intracellular negative regulators phosphotyrosine phosphatases (PTPs) and peroxiredoxins (Prxs), which prolongs RTK signal transduction. This step mostly, but not exclusively (as depicted by an asterisk), involves the endoplasmic reticulum (ER)-associated PTP1B. Spatial restriction of H2O2 is achieved by cytosolic ROS scavengers like Prxs. (b) An ER-centered route of RTK-mediated signal transduction involves NOX4 in the ER membrane and PTP1B. In this context, ER-luminal buildup of H2O2 is controlled by ER-resident PrxIV.

Mentions: Reliable detection of the cellular distribution of H2O2 is a challenging task. The recent development of genetically encoded sensors, which can be expressed in different subcellular compartments, significantly facilitated the monitoring of spatial and temporal changes in H2O2/ROS concentration [43]. For instance, targeted expression of the yellow fluorescent protein-based, ratiometric, and H2O2-sensitive HyPer sensor was used to record the oxidizing environment in the mammalian ER [33, 44–46]. On the basis of the predominantly oxidized state of ER-localized HyPer (HyPerER) and the predominantly reduced state of HyPer on the cytoplasmic surface of the ER, a high [H2O2]ER, which is strictly confined to the lumen of the organelle, has been inferred [44]. Several lines of evidence argue against this interpretation though. First, as detailed in the following paragraph, numerous examples for signaling roles of ER-derived H2O2 are known, which suggest analogy to the critical involvement of Nox-derived H2O2 in receptor tyrosine kinase (RTK) signal transduction at the cell surface [47–50] (Figure 1). Second, the presence of peroxidases in the ER lumen (see below) appears incompatible with a high steady-state [H2O2]ER. Third, the demonstration of aquaporin 8-facilitated entry of H2O2 into the ER [8] suggests that aquaporin 8 can also facilitate exit of ER-derived H2O2 (see also Figure 1). Forth, since the ratiometric readout of HyPer is based on the formation of an intramolecular disulfide bond [51], oxidation of HyPer in the ER could be catalyzed by resident oxidoreductases independently of H2O2. Consistent with this assumption, no effect on HyPerER oxidation was observed upon overexpression of PrxIV or of ER-targeted catalase in pancreatic beta-cells [46]. The increased oxidation of HyPerER observed in response to higher levels of Ero1α [44, 52] can therefore reflect both enhanced oxidation of PDIs and a rise in [H2O2]ER. Thus, the Ero1α-induced increase in oxidation of HyPerER can only be partially reversed by addition of the H2O2 scavenger butylated hydroxyanisole (our unpublished observations). Conversely, increased oxidation of HyPerER in response to NOX4 induction is blunted by coexpression of catalase in the ER [33].


Destroy and exploit: catalyzed removal of hydroperoxides from the endoplasmic reticulum.

Ramming T, Appenzeller-Herzog C - Int J Cell Biol (2013)

RTK signaling involves NOX-derived H2O2 as second messenger. (a) Binding of ligand (L) to receptor tyrosine kinases (RTK) on the cell surface activates NADPH oxidases (NOX) and leads to the generation of extracellular or, following endocytosis, endosomal superoxide (O2−), which can be dismutated to H2O2  (black filled circles). Upon aquaporin 8 (AQP8)-facilitated diffusion across the plasma/endosomal membrane, H2O2 locally inactivates the intracellular negative regulators phosphotyrosine phosphatases (PTPs) and peroxiredoxins (Prxs), which prolongs RTK signal transduction. This step mostly, but not exclusively (as depicted by an asterisk), involves the endoplasmic reticulum (ER)-associated PTP1B. Spatial restriction of H2O2 is achieved by cytosolic ROS scavengers like Prxs. (b) An ER-centered route of RTK-mediated signal transduction involves NOX4 in the ER membrane and PTP1B. In this context, ER-luminal buildup of H2O2 is controlled by ER-resident PrxIV.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3824332&req=5

fig1: RTK signaling involves NOX-derived H2O2 as second messenger. (a) Binding of ligand (L) to receptor tyrosine kinases (RTK) on the cell surface activates NADPH oxidases (NOX) and leads to the generation of extracellular or, following endocytosis, endosomal superoxide (O2−), which can be dismutated to H2O2  (black filled circles). Upon aquaporin 8 (AQP8)-facilitated diffusion across the plasma/endosomal membrane, H2O2 locally inactivates the intracellular negative regulators phosphotyrosine phosphatases (PTPs) and peroxiredoxins (Prxs), which prolongs RTK signal transduction. This step mostly, but not exclusively (as depicted by an asterisk), involves the endoplasmic reticulum (ER)-associated PTP1B. Spatial restriction of H2O2 is achieved by cytosolic ROS scavengers like Prxs. (b) An ER-centered route of RTK-mediated signal transduction involves NOX4 in the ER membrane and PTP1B. In this context, ER-luminal buildup of H2O2 is controlled by ER-resident PrxIV.
Mentions: Reliable detection of the cellular distribution of H2O2 is a challenging task. The recent development of genetically encoded sensors, which can be expressed in different subcellular compartments, significantly facilitated the monitoring of spatial and temporal changes in H2O2/ROS concentration [43]. For instance, targeted expression of the yellow fluorescent protein-based, ratiometric, and H2O2-sensitive HyPer sensor was used to record the oxidizing environment in the mammalian ER [33, 44–46]. On the basis of the predominantly oxidized state of ER-localized HyPer (HyPerER) and the predominantly reduced state of HyPer on the cytoplasmic surface of the ER, a high [H2O2]ER, which is strictly confined to the lumen of the organelle, has been inferred [44]. Several lines of evidence argue against this interpretation though. First, as detailed in the following paragraph, numerous examples for signaling roles of ER-derived H2O2 are known, which suggest analogy to the critical involvement of Nox-derived H2O2 in receptor tyrosine kinase (RTK) signal transduction at the cell surface [47–50] (Figure 1). Second, the presence of peroxidases in the ER lumen (see below) appears incompatible with a high steady-state [H2O2]ER. Third, the demonstration of aquaporin 8-facilitated entry of H2O2 into the ER [8] suggests that aquaporin 8 can also facilitate exit of ER-derived H2O2 (see also Figure 1). Forth, since the ratiometric readout of HyPer is based on the formation of an intramolecular disulfide bond [51], oxidation of HyPer in the ER could be catalyzed by resident oxidoreductases independently of H2O2. Consistent with this assumption, no effect on HyPerER oxidation was observed upon overexpression of PrxIV or of ER-targeted catalase in pancreatic beta-cells [46]. The increased oxidation of HyPerER observed in response to higher levels of Ero1α [44, 52] can therefore reflect both enhanced oxidation of PDIs and a rise in [H2O2]ER. Thus, the Ero1α-induced increase in oxidation of HyPerER can only be partially reversed by addition of the H2O2 scavenger butylated hydroxyanisole (our unpublished observations). Conversely, increased oxidation of HyPerER in response to NOX4 induction is blunted by coexpression of catalase in the ER [33].

Bottom Line: Peroxidases are enzymes that reduce hydroperoxide substrates.Different peroxide sources and reducing substrates for ER peroxidases are critically evaluated.Peroxidase-catalyzed detoxification of hydroperoxides coupled to the productive use of disulfides, for instance, in the ER-associated process of oxidative protein folding, appears to emerge as a common theme.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstr. 50, 4056 Basel, Switzerland.

ABSTRACT
Peroxidases are enzymes that reduce hydroperoxide substrates. In many cases, hydroperoxide reduction is coupled to the formation of a disulfide bond, which is transferred onto specific acceptor molecules, the so-called reducing substrates. As such, peroxidases control the spatiotemporal distribution of diffusible second messengers such as hydrogen peroxide (H2O2) and generate new disulfides. Members of two families of peroxidases, peroxiredoxins (Prxs) and glutathione peroxidases (GPxs), reside in different subcellular compartments or are secreted from cells. This review discusses the properties and physiological roles of PrxIV, GPx7, and GPx8 in the endoplasmic reticulum (ER) of higher eukaryotic cells where H2O2 and-possibly-lipid hydroperoxides are regularly produced. Different peroxide sources and reducing substrates for ER peroxidases are critically evaluated. Peroxidase-catalyzed detoxification of hydroperoxides coupled to the productive use of disulfides, for instance, in the ER-associated process of oxidative protein folding, appears to emerge as a common theme. Nonetheless, in vitro and in vivo studies have demonstrated that individual peroxidases serve specific, nonoverlapping roles in ER physiology.

No MeSH data available.