Aquaporin-3 mediates hydrogen peroxide-dependent responses to environmental stress in colonic epithelia

Thiagarajah, Jay R.; Chang, Jeffrey S.; Goettel, Jeremy A.; Verkman, A. S.; Lencer, Wayne I.

doi:10.1073/pnas.1612921114

Cited by 95 publications

(83 citation statements)

References 41 publications

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“…A pioneering work using HyPer unraveled the role of AQP3 in H 2 O 2 transport and epidermal growth factor (EGF) signaling (31). This function was recently extended to NF-κB signaling in keratinocytes (32) or in response to environmental stresses in colonic epithelia (33). Similarly, AQP8 facilitates cellular accumulation of H 2 O 2 after VEGF stimulation, thereby enhancing PI3K activity and phosphorylation of MAPKs, two essential processes for leukemia cell proliferation (34).…”

Section: Discussionmentioning

confidence: 99%

Aquaporins facilitate hydrogen peroxide entry into guard cells to mediate ABA- and pathogen-triggered stomatal closure

Rodrigues

Reshetnyak

Grondin

et al. 2017

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

268

239

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Stomatal movements are crucial for the control of plant water status and protection against pathogens. Assays on epidermal peels revealed that, similar to abscisic acid (ABA), pathogen-associated molecular pattern (PAMP) flg22 requires the AtPIP2;1 aquaporin to induce stomatal closure. Flg22 also induced an increase in osmotic water permeability (P f ) of guard cell protoplasts through activation of AtPIP2;1. The use of HyPer, a genetic probe for intracellular hydrogen peroxide (H 2 O 2 ), revealed that both ABA and flg22 triggered an accumulation of H 2 O 2 in wild-type but not pip2;1 guard cells. Pretreatment of guard cells with flg22 or ABA facilitated the influx of exogenous H 2 O 2 . Brassinosteroid insensitive 1-associated receptor kinase 1 (BAK1) and open stomata 1 (OST1)/Snf1-related protein kinase 2.6 (SnRK2.6) were both necessary to flg22-induced P f and both phosphorylated AtPIP2;1 on Ser121 in vitro. Accumulation of H 2 O 2 and stomatal closure as induced by flg22 was restored in pip2;1 guard cells by a phosphomimetic form (Ser121Asp) but not by a phosphodeficient form (Ser121Ala) of AtPIP2;1. We propose a mechanism whereby phosphorylation of AtPIP2;1 Ser121 by BAK1 and/or OST1 is triggered in response to flg22 to activate its water and H 2 O 2 transport activities. This work establishes a signaling role of plasma membrane aquaporins in guard cells and potentially in other cellular context involving H 2 O 2 signaling.aquaporin | pathogen | guard cell signaling | hydrogen peroxide | stomatal movement

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Section: Discussionmentioning

confidence: 99%

Aquaporins facilitate hydrogen peroxide entry into guard cells to mediate ABA- and pathogen-triggered stomatal closure

Rodrigues

Reshetnyak

Grondin

et al. 2017

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

268

239

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“…Consistent with this idea, epithelial aquaporin-4 expression has been reported to be enhanced by IL-22 signaling (Pham et al, 2014). However, most studies have failed to identify a role for aquaporins in intestinal water transport, and, recent data suggest that intestinal epithelial aquaporins are more important for transport of bioactive signaling molecules, such as H 2 O 2 , than water (Thiagarajah et al, 2017; Yang et al, 2005). Thus, despite the potential involvement of many processes, including several activated by IL-22, in triggering the water efflux that enhances bacterial clearance, claudin-2 upregulation is the primary mechanism employed in C. rodentium colitis.…”

Section: Discussionmentioning

confidence: 99%

IL-22 Upregulates Epithelial Claudin-2 to Drive Diarrhea and Enteric Pathogen Clearance

Tsai

Zhang

et al. 2017

Cell Host & Microbe

192

200

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SUMMARY Diarrhea is a host response to enteric pathogens, but its impact on pathogenesis remains poorly defined. By infecting mice with the attaching and effacing bacteria Citrobacter rodentium, we defined the mechanisms and contributions of diarrhea and intestinal barrier loss to host defense. Increased permeability occurred within 2 days of infection and coincided with IL-22-dependent upregulation of the epithelial tight junction protein claudin-2. Permeability increases were limited to small molecules, as expected for the paracellular water and Na+ channel formed by claudin-2. Relative to wildtype, claudin-2-deficient mice experienced severe disease, including increased mucosal colonization by C. rodentium, prolonged pathogen shedding, exaggerated cytokine responses, and greater tissue injury. Conversely, transgenic claudin-2 overexpression reduced disease severity. Chemically-induced osmotic diarrhea reduced colitis severity and C. rodentium burden in claudin-2 deficient, but not transgenic, mice, demonstrating that claudin-2-mediated protection is the result of enhanced water efflux. Thus, IL-22-induced claudin-2 upregulation drives diarrhea and pathogen clearance.

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“…Another issue with respect to the proposed involvement of DUOX or other NOX isozymes in cellular redox signalling is the fact that NOX‐derived ROS are generated extracellularly or within phagosomes/endosomes and are thus segregated from their putative cytoplasmic redox‐sensitive targets by a lipid membrane. The recent discovery of aquaporins as selective channels for H 2 O 2 resolves this issue, and aquaporin‐dependent transmembrane H 2 O 2 transfer likely helps confine the oxidative potential of H 2 O 2 to assure specificity in redox signalling (Bertolotti et al ., ; Thiagarajah et al ., ).…”

Section: Mechanisms Of Duox‐mediated Host Defence: From Oxidant‐mediamentioning

confidence: 97%

Dual oxidase: a novel therapeutic target in allergic disease

Vliet

Danyal

Heppner

2018

British J Pharmacology

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NADPH oxidases (NOXs) represent a family of enzymes that mediate regulated cellular production of reactive oxygen species (ROS) and play various functional roles in physiology. Among the NOX family, the dual oxidases DUOX1 and DUOX2 are prominently expressed in epithelial cell types at mucosal surfaces and have therefore been considered to have important roles in innate host defence pathways. Recent studies have revealed important insights into the host defence mechanisms of DUOX enzymes, which control innate immune response pathways in response to either microbial or allergic triggers. In this review, we discuss the current level of understanding with respect to the biological role(s) of DUOX enzymes and the unique role of DUOX1 in mediating innate immune responses to epithelial injury and allergens and in the development of allergic disease. These novel findings highlight DUOX1 as an attractive therapeutic target, and opportunities for the development of selective inhibitor strategies will be discussed. AbbreviationsCPZ, chlorpromazine; DPI, diphenylene iodonium; DUOX, dual oxidase; DUOXA, dual oxidase maturation factor; EGFR, EGF receptor; ER, endoplasmic reticulum; HDM, house dust mite; ILC2, type 2 innate lymphoid cell; LPO, lactoperoxidase; MPO, myeloperoxidase; NOX, NADPH oxidase; NOXA, NOX activator; PDB, protein database; PHD, peroxidase homology domain; ROS, reactive oxygen species; TK, tyrosine kinase; TLR, toll-like receptor; TPO, thyroperoxidase; TRX, thioredoxin IntroductionThe concept of oxidative stress has been widely embraced as a major factor in disease pathology and has fuelled a billion dollar industry based on antioxidant dietary supplements. However, clinical studies using antioxidant supplementation strategies have generally been unsuccessful in attenuating disease risk or progression, and antioxidant supplementation was in some cases found to even worsen pathological outcomes (Ghezzi et al., 2017). This lack of success likely relates to the flawed concept of oxidative stress as a pharmacological target. First, oxidative stress can be brought about by a range of ROS (the commonly used acronym to define this group of reactive metabolites), which can originate from external sources (e.g. environmental pollution and metabolism of xenobiotics) or be generated endogenously by various enzymatic systems, in some cases in a regulated and deliberate fashion to serve important biological functions [e.g. by activation of NADPH oxidases (NOXs)]. Therefore, generic non-selective approaches that indiscriminately suppress ROS may not have the desired outcome. A second flaw with such generic antioxidant approaches is the fact that ROS represent a diverse group of reactive metabolites that each have unique (bio)chemical properties, and it is often unclear to what extent antioxidant supplements counter the action of individual ROS species. To clarify this, it is helpful to distinguish primary from secondary ROS, with primary ROS representing the initial products of (enzymatic) O 2 reduction [i.e. superoxi...

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Aquaporin-3 mediates hydrogen peroxide-dependent responses to environmental stress in colonic epithelia

Cited by 95 publications

References 41 publications

Aquaporins facilitate hydrogen peroxide entry into guard cells to mediate ABA- and pathogen-triggered stomatal closure

Aquaporins facilitate hydrogen peroxide entry into guard cells to mediate ABA- and pathogen-triggered stomatal closure

IL-22 Upregulates Epithelial Claudin-2 to Drive Diarrhea and Enteric Pathogen Clearance

Dual oxidase: a novel therapeutic target in allergic disease

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