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

Heppner, David E.; Janssen–Heininger, Yvonne M. W.; Vliet, Albert van der

doi:10.1016/j.abb.2017.01.008

Cited by 51 publications

(35 citation statements)

References 80 publications

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“…These findings are in line with the prevailing view that ROS act as biological messengers principally through reversible modification of sensitive surface cysteine residues on proteins (7,12). Recently developed methodologies now allow for the identification and quantification of redox-modified protein cysteine residues in intact cells and living tissue (44 -46).…”

Section: Molecular Targets Of Thermogenic Rossupporting

confidence: 73%

Mitochondrial reactive oxygen species and adipose tissue thermogenesis: Bridging physiology and mechanisms

Chouchani

Kazak

Spiegelman

2017

Journal of Biological Chemistry

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Edited by Ruma BanerjeeBrown and beige adipose tissues can catabolize stored energy to generate heat, relying on the principal effector of thermogenesis: uncoupling protein 1 (UCP1). This unique capability could be leveraged as a therapy for metabolic disease. Numerous animal and cellular models have now demonstrated that mitochondrial reactive oxygen species (ROS) signal to support adipocyte thermogenic identity and function. Herein, we contextualize these findings within the established principles of redox signaling and mechanistic studies of UCP1 function. We provide a framework for understanding the role of mitochondrial ROS signaling in thermogenesis together with testable hypotheses for understanding mechanisms and developing therapies. Brown adipose tissue (BAT)2 has long been recognized as a critical thermogenic organ, exemplified by its importance in maintenance of thermal homeostasis in cold environments (1). More recently, clusters of distinct adipocytes with thermogenic capacity have been characterized in white adipose tissue-beige adipocytes-arising in response to various physiological stimuli (2, 3). The thermogenic endowment of these tissues has prompted the reasonable hypothesis that they might be leveraged to catabolize lipid and glucose as an anti-obesity and antidiabetic therapy. As such, recent decades have seen vigorous research into the mechanisms controlling brown and beige adipose tissue identity and function. Thermogenesis in BAT and beige adipose tissue relies on the key effector protein uncoupling protein 1 (UCP1), which can dissipate the electrochemical H ϩ gradient across the inner mitochondrial membrane (4). This UCP1-mediated inducible proton "leak" uncouples protonmotive force from ATP synthesis leading to an increased rate of mitochondrial respiration and heat generation. Additionally, UCP1-independent effectors of thermogenesis have been uncovered in recent years, including utilization of creatine-dependent substrate cycling in beige adipose tissue (5). Of course, expression of UCP1 (or other effectors) per se is not sufficient to drive thermogenesis; these are gas pedals that need a foot, fuel, and an engine. Indeed, thermogenic adipocytes require exceptionally high mitochondrial content and oxidative capacity to support elevated respiration. Moreover, thermogenic respiration is regulated acutely by upstream physiological signals that are required to activate UCP1-mediated uncoupling. So, elucidating the mechanisms that activate thermogenically-poised adipocytes is critical from a therapeutic standpoint.The purpose of this review is to contextualize recent findings that provide evidence for an important signaling role by reactive oxygen species (ROS) in adipose tissue thermogenesis. Remarkably, the importance of ROS signaling in this context has been demonstrated primarily through investigation of redox metabolism using in vivo mouse and intact adipocyte models of thermogenesis. In contrast, studies of ROS and thermogenesis using in vitro and reconstituted systems have provided...

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Section: Molecular Targets Of Thermogenic Rossupporting

confidence: 73%

Mitochondrial reactive oxygen species and adipose tissue thermogenesis: Bridging physiology and mechanisms

Chouchani

Kazak

Spiegelman

2017

Journal of Biological Chemistry

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“…S -glutathionylation) for EGFR regulation is unknown, and it is plausible that these redox modifications might also affect subcellular EGFR trafficking. The cellular mechanisms that mediate EGFR (and other protein) cysteine oxidation are not fully understood[242]. While original studies suggested the involvement of NOX2 in the context of ligand-dependent stimulation, alternative mechanisms of EGFR transactivation involve DUOX1 [148, 243].…”

Section: Duox1 Silencing Emt and Altered Egfr Dynamics: A Dangerousmentioning

confidence: 99%

Paradoxical roles of dual oxidases in cancer biology

Little

Sulovari

Danyal

et al. 2017

Free Radical Biology and Medicine

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Dysregulated oxidative metabolism is a well-recognized aspect of cancer biology, and many therapeutic strategies are based on targeting cancers by altering cellular redox pathways. The NADPH oxidases (NOXes) present an important enzymatic source of biological oxidants, and the expression and activation of several NOX isoforms are frequently dysregulated in many cancers. Cell-based studies have demonstrated a role for several NOX isozymes in controlling cell proliferation and/or cell migration, further supporting a potential contributing role for NOX in promoting cancer. While various NOX isoforms are often upregulated in cancers, paradoxical recent findings indicate that dual oxidases (DUOXes), normally prominently expressed in epithelial lineages, are frequently suppressed in epithelial-derived cancers by epigenetic mechanisms, although the functional relevance of such DUOX silencing has remained unclear. This review will briefly summarize our current understanding regarding the importance of reactive oxygen species (ROS) and NOXes in cancer biology, and focus on recent observations indicating the unique and seemingly opposing roles of DUOX enzymes in cancer biology. We will discuss current knowledge regarding the functional properties of DUOX, and recent studies highlighting mechanistic consequences of DUOX1 loss in lung cancer, and its consequences for tumor invasiveness and current anticancer therapy. Finally, we will also discuss potentially unique roles for the DUOX maturation factors. Overall, a better understanding of mechanisms that regulate DUOX and the functional consequences of DUOX silencing in cancer may offer valuable new diagnostic insights and novel therapeutic opportunities.

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“…Unlike protein tyrosine phosphatases, where the primary oxidation target is the catalytic cysteine at the active site such that oxidation is always inhibitory, kinase families tend to have non-catalytic cysteine residues in unique locations specific to individual kinase families. Thus, function-altering oxidation of kinases can impose a spectrum of changes in structure and function [20, 60] thereby impacting activity, stability or interaction with partner proteins. This is why kinase oxidation can lead to either inhibition or activation depending on the specific protein.…”

Section: Discussionmentioning

confidence: 99%

Endogenous, regulatory cysteine sulfenylation of ERK kinases in response to proliferative signals

Keyes

Parsonage

Yammani

et al. 2017

Free Radical Biology and Medicine

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ERK-dependent signaling is key to many pathways through which extracellular signals are transduced into cell-fate decisions. One conundrum is the way in which disparate signals induce specific responses through a common, ERK-dependent kinase cascade. While studies have revealed intricate ways of controlling ERK signaling through spatiotemporal localization and phosphorylation dynamics, additional modes of ERK regulation undoubtedly remain to be discovered. We hypothesized that fine-tuning of ERK signaling could occur by cysteine oxidation. We report that ERK is actively and directly oxidized by signal-generated H2O2 during proliferative signaling, and that ERK oxidation occurs downstream of a variety of receptor classes tested in four cell lines. Furthermore, within the tested cell lines and proliferative signals, we observed that both activation loop-phosphorylated and non-phosphorylated ERK undergo sulfenylation in cells and that dynamics of ERK sulfenylation is dependent on the cell growth conditions prior to stimulation. We also tested the effect of endogenous ERK oxidation on kinase activity and report that phosphotransfer reactions are reversibly inhibited by oxidation by as much as 80 to 90%, underscoring the importance of considering this additional modification when assessing ERK activation in response to extracellular signals.

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

Cited by 51 publications

References 80 publications

Mitochondrial reactive oxygen species and adipose tissue thermogenesis: Bridging physiology and mechanisms

Mitochondrial reactive oxygen species and adipose tissue thermogenesis: Bridging physiology and mechanisms

Paradoxical roles of dual oxidases in cancer biology

Endogenous, regulatory cysteine sulfenylation of ERK kinases in response to proliferative signals

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