Endosomal hyperacidification in cystic fibrosis is due to defective nitric oxide–cylic GMP signalling cascade

Poschet, Jens F.; Fazio, Joseph Anthony; Timmins, Graham S.; Ornatowski, Wojciech; Perkett, Elizabeth A.; Delgado, Mònica; Deretic, Vojo

doi:10.1038/sj.embor.7400674

Cited by 29 publications

(33 citation statements)

References 31 publications

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“…Only a limited direct overlap or juxtaposition could be seen between GFP-furin and ExoA ( Figure 6A). Instead, the strongest localization of ExoA was with cellubrevin-pHluorin GFP ( Figure 6A), which localizes to the recycling endosome, also hyperacidified in CF cells (8,9). The bulk of cellular furin under steady-state conditions was, as expected, in the Golgi/TGN region, with no discernible differences between CF and CFTR-corrected cells (Supplemental Figure 4).…”

Section: Figurementioning

confidence: 77%

“…A positive feedback loop between TGF-β and furin (21), also observed in our work, amplifies levels of both furin and TGF-β in CF, leading to increased furin amounts detectable by immunoblots. The bulk of cellular furin is located in TGN (17) but it traffics appreciably to and from the plasma membrane, passing through endosomal organelles that are also hyperacidified in CF respiratory epithelial cells (7)(8)(9). In addition to its intracellular action, furin is released from cells to process a number of extracellular substrates (17).…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in CFTR have pleiotropic effects on the function of other ion transporters (2,3). Of particular importance is the CFTR-dependent regulation of the amiloride-sensitive epithelial sodium channel in respiratory epithelial cells (2,3), causing electrolyte and fluid hyperabsorption in the CF lung (2,4) and hyperacidification of intracellular organelles of CF lung epithelial cells including trans-Golgi network (TGN) and endosomal compartments (5)(6)(7)(8)(9)(10). In addition, there is an abundance of proposed defects related to pathology in CF, including defective phagosomal acidification in macrophages (11), altered P. aeruginosa uptake by respiratory epithelial cells (12), impaired glycosylation (13), enhanced Toll-like receptor activation (14), reduced levels of iNOS (15), and disrupted cholesterol transport (16).…”

Section: Introductionmentioning

confidence: 99%

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Elevated furin levels in human cystic fibrosis cells result in hypersusceptibility to exotoxin A–induced cytotoxicity

Ornatowski¹,

Poschet²,

Perkett³

et al. 2007

J. Clin. Invest.

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Progressive pulmonary disease and infections with Pseudomonas aeruginosa remain an intractable problem in cystic fibrosis (CF). At the cellular level, CF is characterized by organellar hyperacidification, which results in altered protein and lipid glycosylation. Altered pH of the trans-Golgi network (TGN) may further disrupt the protein processing and packaging that occurs in this organelle. Here we measured activity of the major TGN endoprotease furin and demonstrated a marked upregulation in human CF cells. Increased furin activity was linked to elevated production in CF of the immunosuppressive and tissue remodeling cytokine TGF-β and its downstream effects, including macrophage deactivation and augmented collagen secretion by epithelial cells. As furin is responsible for the proteolytic processing of a range of endogenous and exogenous substrates including growth factors and bacterial toxins, we determined that elevated furin-dependent activation of exotoxin A caused increased cell death in CF respiratory epithelial cells compared with genetically matched CF transmembrane conductance regulator-corrected cells. Thus elevated furin levels in CF respiratory epithelial cells contributes to bacterial toxin-induced cell death, fibrosis, and local immunosuppression. These data suggest that the use of furin inhibitors may represent a strategy for pharmacotherapy in CF.

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Section: Figurementioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Elevated furin levels in human cystic fibrosis cells result in hypersusceptibility to exotoxin A–induced cytotoxicity

Ornatowski¹,

Poschet²,

Perkett³

et al. 2007

J. Clin. Invest.

Self Cite

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“…However, the building evidence regarding organelle pH and cell signaling is compelling. Recent work linking endocytic acidification and disrupted nitric oxide production directly draws these processes together (37). This same group has also demonstrated that reversing the acidification with chloroquin corrects CF-related changes in TGF-␤1 production (35).…”

Section: Discussionmentioning

confidence: 99%

Altered cholesterol homeostasis in cultured and in vivo models of cystic fibrosis

White

Jiang

Burgess

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Thus it was suggested that impaired iNOS activity could potentially exacerbate autoimmune diseases including colitis, arthritis and multiple sclerosis [91]. In CF patients, lack of iNOS has also been linked to inflammation disorders [92]. Due to its role in inflammation and because it can be measured quickly and non-invasively in the respiratory airways, exhaled NO has become an important diagnostic marker for inflammatory airway conditions such as asthma and bronchitis [93,94].…”

Section: No and Inflammationmentioning

confidence: 99%

Nitric Oxide: A Key Mediator of Biofilm Dispersal with Applications in Infectious Diseases

Barraud¹,

Kelso²,

Rice

et al. 2014

CPD

205

193

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Studies of the biofilm life cycle can identify novel targets and strategies for improving biofilm control measures. Of particular interest are dispersal events, where a subpopulation of cells is released from the biofilm community to search out and colonize new surfaces. Recently, the simple gas and ubiquitous biological signaling molecule nitric oxide (NO) was identified as a key mediator of biofilm dispersal conserved across microbial species. Here, we review the role and mechanisms of NO mediating dispersal in bacterial biofilms, and its potential for novel therapeutics. In contrast to previous attempts using high dose NO aimed at killing pathogens, the use of low, non-toxic NO signals (picomolar to nanomolar range) to disperse biofilms represents an innovative and highly favourable approach to improve infectious disease treatments. Further, several NO-based technologies have been developed that offer a versatile range of solutions to control biofilms, including: (i) NO-generating compounds with short or long half-lives and safe or inert residues, (ii) novel compounds for the targeted delivery of NO to infectious biofilms during systemic treatments, and (iii) novel NO-releasing materials and surface coatings for the prevention and dispersal of biofilms. Overall the use of low levels of NO exploiting its signaling properties to induce dispersal represents an unprecedented and promising strategy for the control of biofilms in clinical and industrial contexts. AbstractStudies of the biofilm life cycle can identify novel targets and strategies for improving biofilm control measures. Of particular interest are dispersal events, where a subpopulation of cells is released from the biofilm community to search out and colonize new surfaces. Recently, the simple gas and ubiquitous biological signaling molecule nitric oxide (NO) was identified as a key mediator of biofilm dispersal conserved across microbial species. Here, we review the role and mechanisms of NO mediating dispersal in bacterial biofilms, and its potential for novel therapeutics. In contrast to previous attempts using high dose NO aimed at killing pathogens, the use of low, non-toxic NO signals (picomolar to nanomolar range) to disperse biofilms represents an innovative and highly favourable approach to improve infectious disease treatments. Further, several NO-based technologies have been developed that offer a versatile range of solutions to control biofilms, including: (i) NO-generating compounds with short or long half-lives and safe or inert residues, (ii) novel compounds for the targeted delivery of NO to infectious biofilms during systemic treatments, and (iii) novel NO-releasing materials and surface coatings for the prevention and dispersal of biofilms. Overall the use of low levels of NO exploiting its signaling properties to induce dispersal represents an unprecedented and promising strategy for the control of biofilms in clinical and industrial contexts. 3 Increased antimicrobial tolerance in biofilms is the basis for chronic infecti...

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Endosomal hyperacidification in cystic fibrosis is due to defective nitric oxide–cylic GMP signalling cascade

Cited by 29 publications

References 31 publications

Elevated furin levels in human cystic fibrosis cells result in hypersusceptibility to exotoxin A–induced cytotoxicity

Elevated furin levels in human cystic fibrosis cells result in hypersusceptibility to exotoxin A–induced cytotoxicity

Altered cholesterol homeostasis in cultured and in vivo models of cystic fibrosis

Nitric Oxide: A Key Mediator of Biofilm Dispersal with Applications in Infectious Diseases

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