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leky-latky/cftr-protein/funkce

Lokalizace

  • At the apical surface of secretory epithelia

B-buňky

  • CFTR regulates B cell activation and lymphoid follicle development
  • Significant increase in well-formed LFs in subjects with CF compared to normal controls
  • Increased B cell activation and proliferation was observed in lung LFs from CF subjects
  • Uninfected Cftr -/- mice had increased lung LFs and BAFF+ and CXCR4+ B cells compared to wild type controls
    • Lung B cells uninfected Cftr -/- mice demonstrated increased MHC class II expression
      • Produced increased IL-6 when stimulated with LPS compared to wild type controls. [21]
  • Data support a direct role for CFTR in B cell activation, proliferation and inflammatory cytokine production
    • That promotes lung LF follicle development in cystic fibrosis. [21]
  • Human B cells that lack CFTR
    • Impaired chloride conductance as is observed in CFTR-deficient epithelial cells [21]

B cell-activating factor of tumor necrosis factor family (BAFF)

  • Is produced by
    • B cells,
    • T cells
    • Myeloid lineage cells [21]
  • Plays an important role in B cell survival and maturation
  • BAFF can bind to three receptors that are constitutively expressed on B cells
    • BAFF-receptor,
    • Transmembrane activator
    • calcium modulator
    • Cyclophilin ligand interactor
    • B-cell maturation antigen [21]
  • BAFF is not produced by B cells at steady state
    • Induced by antigen-activated helper T cells [21]
  • BAFF produced by B cells can work in both an autocrine and paracrine manner
  • Wild type and Cftr -/- mice treated with a neutralizing antibody that blocks BAFF resulted
    • B cell and lung CD4+ regulatory T cell (Treg) depletion
      • Increased the lung bacterial burden in both wild type and CFTR deficient mice infected with P. aeruginosa
      • Bacterial load and lung resistance was higher in the CFTR deficient mice [21]
  • BAFF has been detected in bronchoalveolar lavage (BAL) fluid from patients with CF
    • Most elevated in patients infected with P. aeruginosa
  • BAFF was not detected in BAL fluid from healthy controls
    • BAFF was also shown to be induced in the lungs of wild type mice infected with P. aeruginosa [21]
  • CFTR in the promotion of tertiary lung LF development
    • B cell BAFF and CXCR4 expression and B cell inflammatory cytokine production in the absence of infection. [21]

Alveolar macrophages with silenced CFTR

  • Increased IL-8 secretion
  • Increased NF-kappa B phosphorylation
  • Increased caveolin-1 expression [21]

T helper 2 (Th2)

  • Skewing of CD4 lymphocytes from both patients and Cftr -/- mice has been well described
    • CFTR deficiency has also been linked to diminished regulatory CD4 T cell (Treg) effector function [21]

CFTR and ENaC

  • Essential ion transporters that control airway fluid homeostasis
  • Inverse relationship between CFTR and ENaC functions (Mall and Galietta, 2015)

Hyperactive-ENaC condition

CFTR expression on macrophages

  • Hypothesised that the CFTR may be important for clearance of pathogens and apoptotic neutrophils (Painter et al. 2006)
  • TLR4 is dysregulated in the absence of CFTR (Di Pietro et al. 2017)
  • TLR4 expression is dependent on the heme oxygenase 1/carbon monoxide pathway
    • Interrupted without CFTR (Di Pietro et al. 2017) [23]
  • Abundance of LPS during bacterial infection causes the over-activation of macrophages (Di Pietro et al. 2017) [23]
  • Acidification of endocytic compartments following phagocytosis of bacteria
    • Autonomous integration of CFTR during endocytosis promotes acidification by accumulating Cl-
      • Generating a large enough counterion conductance to maintain H+ gradients (Di et al. 2006) [23]
  • Internalised CFTR be detected in non-CF alveolar macrophages
  • Macrophages from cftr -/- mice
    • Failed to acidify endosome to a bactericidal pH (Di et al. 2006) [23]
  • Despite elevated numbers of macrophages
    • Th cells and other PMNs neutrophils make up over 70% of the cells in the airway during pulmonary exacerbation
    • Directly responsible for irreversible loss of lung function
  • Therefore, better understanding of neutrophil dysfunction may improve effectiveness of therapeutics targeting inflammation. [23]

Cell volume

  • CFTR also regulates NHE3-mediated Na+ absorption by altering epithelial cell volume [18]

Ceramide-rich platforms

  • Some CFTR channels reside in a detergent-resistant membrane (DRM) fraction (Kowalski and Pier, 2004; Wang et al., 2008)
    • This population is increased by tumor necrosis factor (TNF)-alpha (Dudez et al., 2008)
  • Two distinct CFTR channel populations in the plasma membrane of primary human bronchial epithelial cells
    • Transduced with adenovirus containing enhanced GFP (EGFP)-CFTR
    • 1) diffusely distributed
    • 2) in cholesterol-dependent clusters (Abu-Arish et al., 2015)
  • CFTR channels are assumed to be static during physiological regulation due to
    • Tethering by sodium-hydrogen exchanger regulatory factor (NHERF)
    • Scaffold and adapter proteins [22]
  • Lipid raft-like microdomains containing clusters of CFTR channels
    • Are closely associated with
      • The bases of motile cilia
      • With acid sphingomyelinase (ASMase)
        • Enzyme that hydrolyzes plasma membrane sphingomyelin to ceramide [22]
  • ASMase is bound constitutively on the extracellular surface of the membrane
    • Activated by secretagogues
      • Most likely through an autocrine redox signaling mechanism (Zeidan and Hannun, 2007; Li et al., 2012) [22]
  • Activation of extracellular ASMase
    • Promotes the aggregation of CFTR, the ciliary protein centrin2, and ASMase itself [22]
  • Ceramide-rich platforms
    • Are a well-established signaling mechanism under a wide range of pathological conditions (Grassmé et al., 2007; Stancevic and Kolesnick, 2010).
    • Contribute to the physiological regulation of CFTR [22]


Glycoprotein sulfation

  • Reguluje CFTR [17]

CFTR mediates most of the apical HCO3- efflux

  • Recent studies using intracellular pH measurements and patch clamp recording also support CFTR as the main apical HCO3- exit pathway (Kim et al., 2014) [26]
  • Impaired HCO3- secretion from submucosal glands represents another established CF defect.
  • The lack of HCO3- secretion results in
    • Acidic ASL (Coakley et al., 2003; Fischer and Widdicombe, 2006; Song et al., 2006),
    • Compromised bacterial killing (Pezzulo et al., 2012)
    • Reduced mucin expansion during mucin granule release in CF (Quinton, 2010; Widdicombe, 2013).[26]

Intracellular compartments regulate pH

  • Reguluje CFTR [17]

Mozek

  • Widely expressed in the brain (Guo et al., 2009)
  • Prominent regulator of cerebral artery vasoconstriction (Lidington et al., 2019)
    • Modulatory role in ischemic brain injury
  • In cerebral arteries, CFTR mediates a
    • Strong vasodilatory influence
      • By sequestering pro-constrictive molecules away from their receptors (Meissner et al., 2012)
  • www.frontiersin.org/articles/10.3389/fphys.2020.583862/full
  • Inflammatory settings
    • Microvascular CFTR expression is downregulated
      • Leading to a pro-constrictive phenotype (Meissner et al., 2012; Lidington et al., 2019)
  • CFTR expression appears to be largely restricted to the cerebrovascular microcirculation
    • Key advantage of this therapeutic strategy over traditional vasodilators
      • Cerebral perfusion can be increased without a significant impact on mean arterial pressure or other systemic hemodynamic parameters (Lidington et al., 2019).
  • Non-specific neurological manifestations
    • Confusion,
    • Headache,
    • Dizziness are commonly reported symptoms for COVID-19
  • In COVID19 undoubtedly suffered from ischemic injury caused by reduced cerebral perfusion
    • Well-known complication of systemic inflammatory responses
      • For example sepsis (Burkhart et al., 2010)
  • www.frontiersin.org/articles/10.3389/fphys.2020.583862/full
  • Improving neurological symptoms, increasing cerebral perfusion may offer some protection against COVID-19 related stroke
  • Strokes are emerging as a serious complication in COVID-19
    • High incidence of thrombotic complications (Hess et al., 2020; Klok et al., 2020)
    • Increasing cerebral perfusion would be expected to reduce
      • Predilecting factor for coagulation (i.e., low blood flow)
      • Reduce stroke severity in the event of a cerebral thrombosis
  • www.frontiersin.org/articles/10.3389/fphys.2020.583862/full

Regulace Na

  • Enhanced sodium ion absorption in CF
    • Corrected by addition of a wildtype copy of CFTR
  • CFTR and outwardly rectifying chloride channels (ORCCs)
    • CFTR regulates ORCCs by triggering the transport of the potent agonist, ATP, out of the cell
  • CFTR functions to regulate other chloride ion secretory pathways in addition to conducting chloride ion itself.
  • Cystic fibrosis CFTR defective
    • X chloride and bicarbonate secretion
    • Dysregulation of epithelial sodium channels (ENaC)
      • Defective mucociliary clearance
      • Reduced airway surface liquid
      • Exaggerated proinflammatory response
  • www.nature.com/articles/s41435-020-0103-y

Sledování aktivity CFTR proteinu

  • Cellular-based assays of CFTR channel activity such as
    • 125I efflux !!!
    • 6-methoxy-N-(3-sulfopropyl)quinoline (SPQ) fluorescence
    • Whole cell membrane patch recordings [17]

Synergie CFTR and CaCCs

  • Respondto VIP and muscarinic stimuli
  • CAMP enhances Ca2+ release from intracellular stores by stimulating PKA phosphorylation of the inositol trisphosphate (IP3) receptor
  • IP3receptor interacts with IRBIT (IP3 receptor-binding protein released with IP3)
    • Inhibits IP3receptor channel function and is released when the receptor binds IP3 (Andoet al.2003) [20]
  • IRBIT can interact with several acid–base transporters and regulate their activity at the plasma membrane
    • Sodium bicarbonate cotransporter NBCe1-B
    • CFTR(Yanget al.2011)
  • IRBIT can mediate synergism between cAMP and Ca2+ (Parket al.2013) [20]
  • Upregulation of Ca2+signalling in CF cells (Antignyet al.2007; Balghiet al.2011;Martinset al.2011) [20]
  • Functional interactions between CFTR and the Ca2+-activated Cl-channel TMEM16A (Kunzelmannet al.2012). [20]


Transepithelial secretion of Cl-

  • Also depends on three basolateral membrane proteins:
    • The Na+-K+-ATPase to maintain a Na+ gradient
    • The Na+-K+-2Cl- cotransporter for Cl- entry into the cell
    • K+ channels to recycle K+ and maintain the necessary membrane potential to drive Cl- exit across apical membrane Cl- channels
  • At least 3 pharmacologically distinct types of K+ channels contribute to the basolateral membrane K+ conductance:
    • CAMP-activated K+ channel
    • Ca2+-activated K+ channel
    • Maxi K+ channel
  • In addition to CFTR, two other Cl- channels
    • Outwardly rectifying Cl- channel (ORCC)
    • Ca2+-activated Cl- channel
  • Reported to contribute to the apical membrane Cl- conductance
    • Cl- channel gene family (ClC)
    • Voltage-
    • Osmolyte-sensitive anion conductance
  • Activities of each of these basolateral and apical membrane transporters and channels are tightly coordinated
  • Compounds may have inhibitory or stimulatory effects on one or more of these transporters and channels
    • Thereby alter the secretion of Cl-
  • Many of the compounds that have been used to alter the channel activity of CFTR are not specific for CFTR

Vesicle fusion

  • Reguluje CFTR [17]

  • Phagocytic capacity as well as fusion of phagosomes with lysosomes are not affected by mutated CFTR proteins
    • But bacteria are not destroyed and are even able to multiply in CF macrophages

CF neutrophils


Mutations in CFTR a zhoršení funkce lepkem - asociace s celiakií

  • Malfunction triggers the
    • Activation of transglutaminase-2 (TGM2)
    • Inactivation (sequestration) of the Beclin-1 (BECN1) complex [25]
  • Resulting in disabled autophagy
  • An ‘infernal trio’ that locks the cell in a proinflammatory state
    • Anti-homeostatic feedforward loops [25]
  • Stimulation of CFTR function
    • TGM2 inhibition
    • Autophagy stimulation
    • Can be used to treat CF patients [25]
  • Patients with CF have a higher incidence of celiac disease (CD)
  • CFTR defects mice are particularly sensitive to the enteropathogenic effects of gliadin [25]
  • CF patients is exposed to a particularly high antigenic load due to the exocrine pancreatic insufficiency
    • Increased levels of antibodies against dietary antigens
    • Increased fecal calprotectin
    • Alteration of the intestinal microbiota
    • Increased intestinal permeability
  • Cca 4% prevalence of positive anti-TGM2-IgA autoantibodies
    • Prevalence of CD is three times higher in CF patients
  • Mice CFTR knock-out or the F508del-CFTR knock-in mutation
    • Developed signs of ileal inflammation when they were fed with gliadin [25]
  • Inherited CFTR malfunction favors gliadin responsiveness
  • Peptide P57-68 can induce cognate immune responses by T cells and antibodies in (HLA) DQ2/DQ8
  • Peptide P31-43
    • Must ignite an innate immune response in epithelial cells [25]
    • Enters the endosomal compartment
    • Triggers TGM2 activation
    • Perturbs endosomal maturation and trafficking
    • Activates the NF-kappa B pathway [25]
  • CFTR and autophagy are major players in the pathogenesis of CD
  • Intestinal epithelial
    • P31-43 encounters CFTR in clathrin+ vesicles
    • Binds to, and reduces the ATPase activity of the nuclear-binding-domain-1 (NBD1) of CFTR
      • Impairing CFTR function
  • Gliadininduced CFTR malfunction
    • Occurring in CD results
  • P31-43-mediated inhibition of CFTR
    • Drives TGM2 activation that covalently crosslinks P31- 43, CFTR and TGM2 in a trimolecular complex
      • Amplifying the detrimental effects of gliadin
  • CFTR malfunction increase the production of interleukin-15 (IL15)
    • A pro-inflammatory cytokine critical for CD pathogenesis
    • TGM2-mediated NF-kappa B activation

Ery

  • Deformation-induced ATP release from red blood cells requires CFTR activity
  • Inhibitors of CFTR activity
    • Glibenclamide (10 µM)
    • Niflumic acid (20 µM)
  • Resulted in inhibition of deformationinduced ATP release
  • RBCs of healthy humans and COPD patients released ATP in response to mechanical deformation
  • Deformation of RBCs from patients with CF did not result in ATP release
  • ENDOTHELIUM-DERIVED nitric oxide (NO)
    • ATP, is contained in large amounts in red blood cells
  • ATP is released in response to mechanical deformation of RBCs from humans and rabbits could serve as an important determinant of NO synthesis - vascular resistance
  • ATP is a highly charged molecule
    • Does not readily cross cell membranes
    • May exit cells via ‘‘ATP binding cassette’’
  • Removal of glibenclamide from RBCs after a 30-min incubation
    • Did not restore the ability of the RBCs to release ATP in response to mechanical deformation
  • Failure of deformation-induced ATP release from RBCs in cystic fibrosis may lead to a decrease in endogenous NO synthesis and thereby contribute to the development of pulmonary hypertension.
  • May play a previously unrecognized role in the regulation of vascular resistance.
  • [Deformation-induced ATP release from red blood cells requires CFTR activity, RANDY S. SPRAGUE, MARY L. ELLSWORTH, ALAN H. STEPHENSON, MARY E. KLEINHENZ, AND ANDREW J. LONIGRO, Departments of Medicine and Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri 63104 ]
  • Functions as a cAMP-activated chloride ion channel in fluid-transporting epithelia
  • Hydrolyzes ATP to pump substrates, such as
    • Ions, vitamins, drugs, toxins, and peptides across biological membranes (Riordan, 2008)
    • Transport jodu, glutathionu, SCN- do plicních sekretů
  • Nuclear factor kappa B and mitogen-activated protein kinase (MAPK) signaling
    • Were activated following high glucose treatment
  • CFTR attenuates high glucose-induced endothelial cell oxidative stress and inflammation
    • Through inactivation of NF-kappa B and MAPK signaling
    • Elevation of CFRT expression may be a novel strategy in preventing endothelial dysfunction in diabetes
  • www.spandidos-publications.com/10.3892/ijmm.2018.3547

Kůže

  • Thus changes in cellular metabolism and cellular redox potential can influence the activity of CFTR [17]


  • Fluid secretion into the airway lumen is driven by Cl- transport

Dual effect on the channel activity


CFTR as a major sensor of stress

  • Alerts the autophagy machinery when a stressful event risks to perturb cellular physiology
  • CFTR malfunction in macrophages of CF patients
    • Compromises the autophagy-mediated clearance of Pseudomonas aeruginosa and Burkholderia cepacia [25]
  • Defective bacterial clearance
    • Can be reverted by restoring CFTR function at the cell surface
  • Interaction of functional CFTR with caveolin-1 (CAV1) in airways
    • Required to avoid excessive Toll-like receptor 4 (TLR4) signaling upon exposure to bacterial products [25]

Štítnice

  • Potential candidates for mediating I- efflux at the apical membrane of thyrocytes.
  • CFTR is permeable to I-
    • Expressed in the thyroid
    • May be involved, at least in part, in apical I- efflux
  • CF patients may be more likely to develop subclinical hypothyroidism
    • Mechanism of reduced serum TH concentrations in CF has not yet been elucidated
  • academic.oup.com/edrv/article/35/1/106/2354709

Střevo

  • Recognization of the role of cystic fibrosis transmembrane regulator (CFTR) and calcium-activated chloride channels (CaCCs) in intestine fluid secretion and motility modulation makes CFTR and CaCCs promising molecule targets for anti-constipation therapy. [11]


CFTR a regulace tonu cév

  • CFTR transports extracellular S1P across the plasma membrane for degradation
  • Disruption of any of these aspects would be expected to affect S1P signaling
    • This leads us to speculate that CFTR dysfunction could play a causal role in pathological conditions that are associated with altered S1P signaling
  • Prominent enhancement of S1P signaling in resistance arteries under the condition of heart failure (HF)
  • Inverse relationship between microvascular CFTR activity and S1P signaling is manifest
    • S1P-dependent vasomotor responses and myogenic tone
  • Mice with HF
    • S1P is known to mediate enhanced peripheral vascular resistance
  • www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.111.047316
  • Normally, the protein allows movement of chloride and thiocyanate ions (with a negative charge)
    • Out of an epithelial cell into the Airway Surface Liquid and mucus
  • Positively charged sodium ions follow passively
    • Increasing the total electrolyte concentration in the mucus,
    • Resulting in the movement of water out of the cell via osmosis.
en.wikipedia.org/wiki/Cystic_fibrosis_transmembrane_conductance_regulator

Vazodilatace plicních cév

  • Activation of the CFTR in IPA leads to endothelium-independent vasorelaxation. The present study is the first to show the presence and function of CFTR channels in primary cultured PASMCs and their implications for pulmonary vasorelaxation.

O úroveň výše

Poslední aktualizace: 26. 2. 2021 14:05:15