Agonists that stimulate secretion promote the recruitment of CFTR into membrane lipid microdomains

Abu‐Arish, Asmahan; Pandžić, Elvis; Kim, Dusik; Tseng, Hsin Wei; Wiseman, Paul W.; Hanrahan, John W.

doi:10.1085/jgp.201812143

Cited by 23 publications

(54 citation statements)

References 80 publications

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“…The effects of altered membrane microdomain abundance on relative fluidity and stability of transmembrane receptors involved in inflammatory responses and activity of ion channels remains poorly understood (15,45,46). Notably, Abu-Arish and colleagues recently demonstrated that epithelial cells respond to secretagogues by forming clusters of CFTR in ceramide-rich membrane microdomains via an acid sphingomyelinase-dependent mechanism to increase transepithelial secretion (47). We found that reducing ceramide in CF epithelial cells, via rhAC treatment, was associated with reduced TNFR1 expression, decreased cRel nuclear localization, and less IL-8 production.…”

Section: Discussionmentioning

confidence: 99%

Recombinant Acid Ceramidase Reduces Inflammation and Infection in Cystic Fibrosis

Gardner

Haq

Simpson

et al. 2020

Am J Respir Crit Care Med

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Rationale: In cystic fibrosis the major cause of morbidity and mortality is lung disease characterized by inflammation and infection. The influence of sphingolipid metabolism is poorly understood with a lack of studies using human airway model systems. Objectives: To investigate sphingolipid metabolism in cystic fibrosis and the effects of treatment with recombinant human acid ceramidase on inflammation and infection. Methods: Sphingolipids were measured using mass spectrometry in fully differentiated cultures of primary human airway epithelial cells and cocultures with Pseudomonas aeruginosa. In situ activity assays, Western blotting, and quantitative PCR were used to investigate function and expression of ceramidase and sphingomyelinase. Effects of treatment with recombinant human acid ceramidase on sphingolipid profile and inflammatory mediator production were assessed in cell cultures and murine models. Measurements and Main Results: Ceramide is increased in cystic fibrosis airway epithelium owing to differential function of enzymes regulating sphingolipid metabolism. Sphingosine, a metabolite of ceramide with antimicrobial properties, is not upregulated in response to P. aeruginosa by cystic fibrosis airway epithelia. Tumor necrosis factor receptor 1 is increased in cystic fibrosis epithelia and activates NF-kB signaling, generating inflammation. Treatment with recombinant human acid ceramidase, to decrease ceramide, reduced both inflammatory mediator production and susceptibility to infection. Conclusions: Sphingolipid metabolism is altered in airway epithelial cells cultured from people with cystic fibrosis. Treatment with recombinant acid ceramidase ameliorates the two pivotal features of cystic fibrosis lung disease, inflammation and infection, and thus represents a therapeutic approach worthy of further exploration.

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Section: Discussionmentioning

confidence: 99%

Recombinant Acid Ceramidase Reduces Inflammation and Infection in Cystic Fibrosis

Gardner

Haq

Simpson

et al. 2020

Am J Respir Crit Care Med

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“…In the last 5 years, several studies have investigated the role of lipid composition and dynamics of the plasma membrane in the trafficking of cystic fibrosis (CF) transmembrane conductance regulator (CFTR), the anion transporter defective in CF. The role of cholesterol and ceramides, including short-chain ones (1), in the formation of CFTR clusters in the plasma membrane has been reported (2), as well as the stabilization of CFTR triggered by phosphatidylserines (3). An important contribution to CFTR stability at the cell membrane also comes from the action of flippases (4), enzymes known to regulate the movement of phospholipids across the cell membrane.…”

Section: Introductionmentioning

confidence: 99%

Distinctive lipid signatures of bronchial epithelial cells associated with cystic fibrosis drugs, including Trikafta

Liessi¹,

Pesce²,

Braccia³

et al. 2020

JCI Insight

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“…Prior to this study, cholesterol was only thought to act indirectly rather than directly to regulate the function of CFTR. According to a recent study by Hanrahan and colleagues, secretagogues, like vasoactive intestinal peptide acted to promote association of CFTR with cholesterol-containing clusters on the apical surface of respiratory epithelial cells [57]. This clustering restricts the lateral mobility of CFTR, thereby enabling its efficient incorporation into macromolecular complexes important for phosphorylation-dependent regulation and integration with larger, ceramide rich platforms [57].…”

Section: Discussionmentioning

confidence: 99%

Cholesterol Interaction Directly Enhances Intrinsic Activity of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

Chin

Ramjeesingh

Hung

et al. 2019

Cells

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The recent cryo-electron microscopy structures of zebrafish and the human cystic fibrosis transmembrane conductance regulator (CFTR) provided unprecedented insights into putative mechanisms underlying gating of its anion channel activity. Interestingly, despite predictions based on channel activity measurements in biological membranes, the structure of the detergent purified, phosphorylated, and ATP-bound human CFTR protein did not reveal a stably open conduction pathway. This study tested the hypothesis that the functional properties of the detergent solubilized CFTR protein used for structural determinations are different from those exhibited by CFTR purified under conditions that retain associated lipids native to the membrane. It was found that CFTR purified together with phospholipids and cholesterol using amphipol: A8-35, exhibited higher rates of catalytic activity, phosphorylation dependent channel activation and potentiation by the therapeutic compound, ivacaftor, than did CFTR purified in detergent. The catalytic activity of phosphorylated CFTR detergent micelles was rescued by the addition of phospholipids plus cholesterol, but not by phospholipids alone, arguing for a specific role for cholesterol in modulating this function. In summary, these studies highlight the importance of lipid interactions in the intrinsic activities and pharmacological potentiation of CFTR.

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Agonists that stimulate secretion promote the recruitment of CFTR into membrane lipid microdomains

Cited by 23 publications

References 80 publications

Recombinant Acid Ceramidase Reduces Inflammation and Infection in Cystic Fibrosis

Recombinant Acid Ceramidase Reduces Inflammation and Infection in Cystic Fibrosis

Distinctive lipid signatures of bronchial epithelial cells associated with cystic fibrosis drugs, including Trikafta

Cholesterol Interaction Directly Enhances Intrinsic Activity of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

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