scholarly journals Metaproteomics to Decipher CF Host-Microbiota Interactions: Overview, Challenges and Future Perspectives

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 892
Author(s):  
Pauline Hardouin ◽  
Raphael Chiron ◽  
Hélène Marchandin ◽  
Jean Armengaud ◽  
Lucia Grenga
Keyword(s):  
Cystic Fibrosis ◽  
Treatment Outcome ◽  
Chronic Infection ◽  
Phenotypic Variability ◽  
Anion Channel ◽  
Hereditary Disease ◽  
Transmembrane Conductance Regulator ◽  
Future Perspectives ◽  
Transmembrane Conductance ◽  
Cf Transmembrane Conductance Regulator

Cystic fibrosis (CF) is a hereditary disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, triggering dysfunction of the anion channel in several organs including the lung and gut. The main cause of morbidity and mortality is chronic infection. The microbiota is now included among the additional factors that could contribute to the exacerbation of patient symptoms, to treatment outcome, and more generally to the phenotypic variability observed in CF patients. In recent years, various omics tools have started to shed new light on microbial communities associated with CF and host–microbiota interactions. In this context, proteomics targets the key effectors of the responses from organisms, and thus their phenotypes. Recent advances are promising in terms of gaining insights into the CF microbiota and its relation with the host. This review provides an overview of the contributions made by proteomics and metaproteomics to our knowledge of the complex host–microbiota partnership in CF. Considering the strengths and weaknesses of proteomics-based approaches in profiling the microbiota in the context of other diseases, we illustrate their potential and discuss possible strategies to overcome their limitations in monitoring both the respiratory and intestinal microbiota in sample from patients with CF.

scholarly journals COPII-dependent export of cystic fibrosis transmembrane conductance regulator from the ER uses a di-acidic exit code

2004 ◽  
Vol 167 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Xiaodong Wang ◽  
Jeanne Matteson ◽  
Yu An ◽  
Bryan Moyer ◽  
Jin-San Yoo ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Hereditary Disease ◽  
Mutant Form ◽  
Transmembrane Conductance Regulator ◽  
Wild Type ◽  
Transmembrane Conductance ◽  
Primary Defect ◽  
Cf Transmembrane Conductance Regulator ◽  
Er Export ◽  
Cystic Fibrosis Transmembrane

Cystic fibrosis (CF) is a childhood hereditary disease in which the most common mutant form of the CF transmembrane conductance regulator (CFTR) ΔF508 fails to exit the endoplasmic reticulum (ER). Export of wild-type CFTR from the ER requires the coat complex II (COPII) machinery, as it is sensitive to Sar1 mutants that disrupt normal coat assembly and disassembly. In contrast, COPII is not used to deliver CFTR to ER-associated degradation. We find that exit of wild-type CFTR from the ER is blocked by mutation of a consensus di-acidic ER exit motif present in the first nucleotide binding domain. Mutation of the code disrupts interaction with the COPII coat selection complex Sec23/Sec24. We propose that the di-acidic exit code plays a key role in linking CFTR to the COPII coat machinery and is the primary defect responsible for CF in ΔF508-expressing patients.

scholarly journals Postnatal airway growth in cystic fibrosis piglets

2017 ◽  
Vol 123 (3) ◽  
pp. 526-533 ◽  
Author(s):  
Ryan J. Adam ◽  
Mahmoud H. Abou Alaiwa ◽  
Drake C. Bouzek ◽  
Daniel P. Cook ◽  
Nicholas D. Gansemer ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Lung Volume ◽  
Growth And Development ◽  
Anion Channel ◽  
Postnatal Period ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Disease Pathogenesis ◽  
Cf Transmembrane Conductance Regulator

Mutations in the gene encoding the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) anion channel cause CF. The leading cause of death in the CF population is lung disease. Increasing evidence suggests that in utero airway development is CFTR-dependent and that developmental abnormalities may contribute to CF lung disease. However, relatively little is known about postnatal CF airway growth, largely because such studies are limited in humans. Therefore, we examined airway growth and lung volume in a porcine model of CF. We hypothesized that CF pigs would have abnormal postnatal airway growth. To test this hypothesis, we performed CT-based airway and lung volume measurements in 3-wk-old non-CF and CF pigs. We found that 3-wk-old CF pigs had tracheas of reduced caliber and irregular shape. Their bronchial lumens were reduced in size proximally but not distally, were irregularly shaped, and had reduced distensibility. Our data suggest that lack of CFTR results in aberrant postnatal airway growth and development, which could contribute to CF lung disease pathogenesis. NEW & NOTEWORTHY This CT scan-based study of airway morphometry in the cystic fibrosis (CF) postnatal period is unique, as analogous studies in humans are greatly limited for ethical and technical reasons. Findings such as reduced airway lumen area and irregular caliber suggest that airway growth and development are CF transmembrane conductance regulator-dependent and that airway growth defects may contribute to CF lung disease pathogenesis.

Liquid secretion inhibitors reduce mucociliary transport in glandular airways

2002 ◽  
Vol 283 (2) ◽  
pp. L329-L335 ◽  
Author(s):  
Stephen T. Ballard ◽  
Laura Trout ◽  
Anil Mehta ◽  
Sarah K. Inglis
Keyword(s):  
Beat Frequency ◽  
Anion Channel ◽  
Ciliary Beat Frequency ◽  
Mucociliary Transport ◽  
Transmembrane Conductance Regulator ◽  
Inhibitory Effects ◽  
Transmembrane Conductance ◽  
Regulator Protein ◽  
Liquid Absorption ◽  
Cf Transmembrane Conductance Regulator

Because of its possible importance in cystic fibrosis (CF) pulmonary pathogenesis, the effect of anion and liquid secretion inhibitors on airway mucociliary transport was examined. When excised porcine tracheas were treated with ACh to induce gland liquid secretion, the rate of mucociliary transport was increased nearly threefold from 2.5 ± 0.5 to 6.8 ± 0.8 mm/min. Pretreatment with both bumetanide and dimethylamiloride (DMA), to respectively inhibit Cl− and HCO[Formula: see text]secretion, significantly reduced mucociliary transport in the presence of ACh by 92%. Pretreatment with the anion channel blocker 5-nitro-2-(3-phenylpropylamino)benzoic acid similarly reduced mucociliary transport in ACh-treated airways by 97%. These agents did not, however, reduce ciliary beat frequency. Luminal application of benzamil to block liquid absorption significantly attenuated the inhibitory effects of bumetanide and DMA on mucociliary transport. We conclude that anion and liquid secretion is essential for normal mucociliary transport in glandular airways. Because the CF transmembrane conductance regulator protein likely mediates Cl−, HCO[Formula: see text], and liquid secretion in normal glands, we speculate that impairment of gland liquid secretion significantly contributes to defective mucociliary transport in CF.

scholarly journals GM1 as Adjuvant of Innovative Therapies for Cystic Fibrosis Disease

2020 ◽  
Vol 21 (12) ◽  
pp. 4486 ◽  
Author(s):  
Giulia Mancini ◽  
Nicoletta Loberto ◽  
Debora Olioso ◽  
Maria Cristina Dechecchi ◽  
Giulio Cabrini ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Anion Channel ◽  
Apical Plasma Membrane ◽  
Multiple Drug ◽  
Common Mutation ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Starting Point ◽  
Innovative Therapies ◽  
Cftr Protein

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein is expressed at the apical plasma membrane (PM) of different epithelial cells. The most common mutation responsible for the onset of cystic fibrosis (CF), F508del, inhibits the biosynthesis and transport of the protein at PM, and also presents gating and stability defects of the membrane anion channel upon its rescue by the use of correctors and potentiators. This prompted a multiple drug strategy for F508delCFTR aimed simultaneously at its rescue, functional potentiation and PM stabilization. Since ganglioside GM1 is involved in the functional stabilization of transmembrane proteins, we investigated its role as an adjuvant to increase the effectiveness of CFTR modulators. According to our results, we found that GM1 resides in the same PM microenvironment as CFTR. In CF cells, the expression of the mutated channel is accompanied by a decrease in the PM GM1 content. Interestingly, by the exogenous administration of GM1, it becomes a component of the PM, reducing the destabilizing effect of the potentiator VX-770 on rescued CFTR protein expression/function and improving its stabilization. This evidence could represent a starting point for developing innovative therapeutic strategies based on the co-administration of GM1, correctors and potentiators, with the aim of improving F508del CFTR function.

scholarly journals VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1

2013 ◽  
Vol 24 (19) ◽  
pp. 3016-3024 ◽  
Author(s):  
Hong Yu Ren ◽  
Diane E. Grove ◽  
Oxana De La Rosa ◽  
Scott A. Houck ◽  
Pattarawut Sopha ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Chloride Transport ◽  
Genetic Disorder ◽  
Missense Mutations ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Regulator Protein ◽  
Folding Defect ◽  
Membrane Spanning ◽  
Cf Transmembrane Conductance Regulator

Cystic fibrosis (CF) is a fatal genetic disorder associated with defective hydration of lung airways due to the loss of chloride transport through the CF transmembrane conductance regulator protein (CFTR). CFTR contains two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory domain, and its channel assembly requires multiple interdomain contacts. The most common CF-causing mutation, F508del, occurs in NBD1 and results in misfolding and premature degradation of F508del-CFTR. VX-809 is an investigational CFTR corrector that partially restores CFTR function in people who are homozygous for F508del-CFTR. To identify the folding defect(s) in F508del-CFTR that must be repaired to treat CF, we explored the mechanism of VX-809 action. VX-809 stabilized an N-terminal domain in CFTR that contains only MSD1 and efficaciously restored function to CFTR forms that have missense mutations in MSD1. The action of VX-809 on MSD1 appears to suppress folding defects in F508del-CFTR by enhancing interactions among the NBD1, MSD1, and MSD2 domains. The ability of VX-809 to correct F508del-CFTR is enhanced when combined with mutations that improve F508del-NBD1 interaction with MSD2. These data suggest that the use of VX-809 in combination with an additional CFTR corrector that suppresses folding defects downstream of MSD1 may further enhance CFTR function in people with F508del-CFTR.

scholarly journals Maturation and function of cystic fibrosis transmembrane conductance regulator variants bearing mutations in putative nucleotide-binding domains 1 and 2.

1991 ◽  
Vol 11 (8) ◽  
pp. 3886-3893 ◽  
Author(s):  
R J Gregory ◽  
D P Rich ◽  
S H Cheng ◽  
D W Souza ◽  
S Paul ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Amino Acid ◽  
Functional Activity ◽  
Nucleotide Binding ◽  
Missense Mutations ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Fluorescence Measurements ◽  
Cf Transmembrane Conductance Regulator ◽  
Altered Proteins

One feature of the mutations thus far found to be associated with the disease cystic fibrosis (CF) is that many of them are clustered within the first nucleotide-binding domain (NBD) of the CF transmembrane conductance regulator (CFTR). We sought to discover the molecular basis for this clustering by introducing into the two NBDs of CFTR mutations either mimicking amino acid changes associated with CF or altering residues within highly conserved motifs. Synthesis and maturation of the mutant CFTR were studied by transient expression in COS cells. The ability of the altered proteins to generate cyclic AMP-stimulated anion efflux was assessed by using 6-methoxy-N-(sulfopropyl) quinolinium (SPQ) fluorescence measurements in HeLa cells expressing mutated plasmids. The results show that (i) all CF-associated mutants, with one exception, lack functional activity as measured in the SPQ assay, (ii) mutations in NBD1 are more sensitive to the effects of the same amino acid change than are the corresponding mutations in NBD2, (iii) cells transfected with plasmids bearing CF-associated mutations commonly but not exclusively lack mature CFTR, (iv) NBD mutants lacking mature CFTR fail to activate Cl- channels, and (v) the glycosylation of CFTR, per se, is not required for CFTR function. We reason that the structure of NBD1 itself or of the surrounding domains renders it particularly sensitive to mutational changes. As a result, most NBD1 mutants, but only a few NBD2 mutants, fail to mature or lack functional activity. These findings are consistent with the observed uneven distribution of CFTR missense mutations between NBD1 and NBD2 of CF patients.

scholarly journals Dysfunctional cystic fibrosis transmembrane conductance regulator inhibits phagocytosis of apoptotic cells with proinflammatory consequences

2009 ◽  
Vol 297 (4) ◽  
pp. L677-L686 ◽  
Author(s):  
R. William Vandivier ◽  
Tiffany R. Richens ◽  
Sarah A. Horstmann ◽  
Aimee M. deCathelineau ◽  
Moumita Ghosh ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Rho Kinase ◽  
Negative Regulator ◽  
Apoptotic Cells ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Altered Expression ◽  
Proinflammatory Mediators ◽  
Downstream Effector ◽  
Cf Transmembrane Conductance Regulator

Cystic fibrosis (CF) is caused by mutated CF transmembrane conductance regulator (CFTR) and is characterized by robust airway inflammation and accumulation of apoptotic cells. Phagocytosis of apoptotic cells (efferocytosis) is a pivotal regulator of inflammation, because it prevents postapoptotic necrosis and actively suppresses release of a variety of proinflammatory mediators, including IL-8. Because CF is associated with accumulation of apoptotic cells, inappropriate levels of IL-8, and robust inflammation, we sought to determine whether CFTR deficiency specifically impairs efferocytosis and its regulation of inflammatory mediator release. Here we show that CFTR deficiency directly interferes with efferocytosis by airway epithelium, an effect that is not due to altered binding of apoptotic cells to epithelial cells or altered expression of efferocytosis receptors. In contrast, expression of RhoA, a known negative regulator of efferocytosis, is substantially increased in CFTR-deficient cells, and inhibitors of RhoA or its downstream effector Rho kinase normalize efferocytosis in these cells. Impaired efferocytosis appears to be mediated through an amiloride-sensitive ion channel, because amiloride restores phagocytic competency in CFTR-deficient cells. Finally, ineffective efferocytosis in CFTR-deficient cells appears to have proinflammatory consequences, because apoptotic cells enhance IL-8 release by these cells, but not by wild-type controls. Therefore, in CF, dysregulated efferocytosis may lead to accumulation of apoptotic cells and impaired regulation of the inflammatory response and, ultimately, may suggest a new therapeutic target.

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