Hyperacidification of Cellubrevin Endocytic Compartments and Defective Endosomal Recycling in Cystic Fibrosis Respiratory Epithelial Cells

Poschet, Jens F.; Skidmore, Jennifer; Boucher, J C; Firoved, Aaron M.; Dyke, Rebecca W. Van; Deretic, Vojo

doi:10.1074/jbc.m105441200

Cited by 42 publications

(54 citation statements)

References 44 publications

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“…Accordingly, an acidification defect was found in transGolgi and prelysosomal compartments in immortalized respiratory epithelial cells and nasal polyps from patients with CF (16). More recently, however, enhanced rather than decreased acidification was reported in endosomes of CF respiratory epithelial cells (17). Our fractionation data show that, in mouse kidney, CFTR co-distributes with ClC-5 and the V-ATPase in PT (C through F) kidneys.…”

Section: Discussionmentioning

confidence: 72%

“…Taken together, these data suggest that the lack of CFTR in the S3 segment is reflected by an instability of cubilin in the apical membrane, leading to its accelerated shedding in the urine. Although the lack of suitable reagents prevented investigation of the specific role of amnionless in the process, it is tempting to hypothesize that such cubilin instability could be due to the improper processing or trafficking of one of its partners in relation with the lack of CFTR in that nephron segment (15,17). Of note, a decrease in cubilin has been observed in the small intestine of the CFTR null (Cftr tmlUNC ) mouse, which may explain a reduced vitamin B 12 absorption in patients with CF (38).…”

Section: Studies In Clcn5mentioning

confidence: 99%

“…Inhibition of endocytic activity, as well as defective acidification in trans-Golgi and prelysosomal compartments, has been reported in CF cells (16). However, the exact role of CFTR in regulating organelle pH remains controversial, with hyper-rather than hypo-acidification suggested to occur in CF respiratory epithelial cells (17). Recent findings about the endosomal protein ClC-5, which belongs to the CLC family of Cl Ϫ channels/exchangers, have provided insights into the role of anion transporters in PT cells (18).…”

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confidence: 99%

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Cystic Fibrosis Is Associated with a Defect in Apical Receptor–Mediated Endocytosis in Mouse and Human Kidney

Jouret¹,

Bernard²,

Hermans³

et al. 2007

Journal of the American Society of Nephrology

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Inactivation of the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR) causes cystic fibrosis (CF).Although CFTR is expressed in the kidney, no overwhelming renal phenotype has been documented in patients with CF. This study investigated the expression, subcellular distribution, and processing of CFTR in the kidney; used various mouse models to assess the role of CFTR in proximal tubule (PT) endocytosis; and tested the relevance of these findings in patients with CF. The level of CFTR mRNA in mouse kidney approached that found in lung. CFTR was located in the apical area of PT cells, with a maximal intensity in the straight part (S3) of the PT. Fractionation showed that CFTR co-distributed with the chloride/proton exchanger ClC-5 in PT endosomes. Cftr ؊/؊ mice showed impaired 125 I-␤ 2 -microglobulin uptake, together with a decreased amount of the multiligand receptor cubilin in the S3 segment and a significant loss of cubilin and its low molecular weight (LMW) ligands into the urine. Defective receptor-mediated endocytosis was found less consistently in Cftr ⌬F/⌬F mice, characterized by a large phenotypic heterogeneity and moderate versus mice that lacked ClC-5. A significant LMW proteinuria (and particularly transferrinuria) also was documented in a cohort of patients with CF but not in patients with asthma and chronic lung inflammation. In conclusion, CFTR inactivation leads to a moderate defect in receptor-mediated PT endocytosis, associated with a cubilin defect and a significant LMW proteinuria in mouse and human. The magnitude of the endocytosis defect that is caused by CFTR versus ClC-5 loss likely reflects functional heterogeneity along the PT.

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Section: Discussionmentioning

confidence: 72%

Section: Studies In Clcn5mentioning

confidence: 99%

mentioning

confidence: 99%

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Cystic Fibrosis Is Associated with a Defect in Apical Receptor–Mediated Endocytosis in Mouse and Human Kidney

Jouret¹,

Bernard²,

Hermans³

et al. 2007

Journal of the American Society of Nephrology

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“…This charge movement may permit additional entry of protons into the endosome through other voltage-gated channels such as vesicular ClC or the vesicular ATPase proton pump. In other words, we hypothesize that NaV1.5 mediates physiologic endosomal hyperacidification in the macrophage that is comparable to pathologic endosomal hyperacidification seen in epithelial cells from patients with cystic fibrosis (27). In cystic fibrosis, hyperacidification of epithelial endosomes seems to occur through a lack of inhibition of the endosomal sodium exchanger, similar to the actions of endosomal NaV1.5 seen here, that moves sodium of the endosome to permit enhanced entry of protons.…”

Section: Discussionmentioning

confidence: 86%

Expression of the Voltage-Gated Sodium Channel NaV1.5 in the Macrophage Late Endosome Regulates Endosomal Acidification

Carrithers¹,

Dib‐Hajj

Carrithers³

et al. 2007

The Journal of Immunology

119

122

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Voltage-gated sodium channels expressed on the plasma membrane activate rapidly in response to changes in membrane potential in cells with excitable membranes such as muscle and neurons. Macrophages also require rapid signaling mechanisms as the first line of defense against invasion by microorganisms. In this study, our goal was to examine the role of intracellular voltage-gated sodium channels in macrophage function. We demonstrate that the cardiac voltage-gated sodium channel, NaV1.5, is expressed on the late endosome, but not the plasma membrane, in a human monocytic cell line, THP-1, and primary human monocyte-derived macrophages. Although the neuronal channel, NaV1.6, is also expressed intracellularly, it has a distinct subcellular localization. In primed cells, NaV1.5 regulates phagocytosis and endosomal pH during LPS-mediated endosomal acidification. Activation of the endosomal channel causes sodium efflux and decreased intraendosomal pH. These results demonstrate a functionally relevant intracellular voltage-gated sodium channel and reveal a novel mechanism to regulate macrophage endosomal acidification.

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“…In addition, a dileucine (LL) motif, also in the C terminus, is important for CFTR endocytosis (20,24). In CF cells, there appears to be a general defect in endocytic trafficking, including a decrease in the endocytic recycling of the transferrin receptor (TfR) (25).…”

mentioning

confidence: 99%

Myosin VI Regulates Endocytosis of the Cystic Fibrosis Transmembrane Conductance Regulator

Swiatecka‐Urban

Boyd

Coutermarsh

et al. 2004

Journal of Biological Chemistry

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The cystic fibrosis transmembrane conductance regulator (CFTR) is a cyclic AMP-regulated Cl ؊ channel expressed in the apical plasma membrane in fluid-transporting epithelia. Although CFTR is rapidly endocytosed from the apical membrane of polarized epithelial cells and efficiently recycled back to the plasma membrane, little is known about the molecular mechanisms regulating CFTR endocytosis and endocytic recycling. Myosin VI, an actin-dependent, minus-end directed mechanoenzyme, has been implicated in clathrin-mediated endocytosis in epithelial cells. The goal of this study was to determine whether myosin VI regulates CFTR endocytosis. Endogenous, apical membrane CFTR in polarized human airway epithelial cells (Calu-3) formed a complex with myosin VI, the myosin VI adaptor protein Disabled 2 (Dab2), and clathrin. The tail domain of myosin VI, a dominant-negative recombinant fragment, displaced endogenous myosin VI from interacting with Dab2 and CFTR and increased the expression of CFTR in the plasma membrane by reducing CFTR endocytosis. However, the myosin VI tail fragment had no effect on the recycling of endocytosed CFTR or on fluid-phase endocytosis. CFTR endocytosis was decreased by cytochalasin D, an actin-filament depolymerizing agent. Taken together, these data indicate that myosin VI and Dab2 facilitate CFTR endocytosis by a mechanism that requires actin filaments.

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Hyperacidification of Cellubrevin Endocytic Compartments and Defective Endosomal Recycling in Cystic Fibrosis Respiratory Epithelial Cells

Cited by 42 publications

References 44 publications

Cystic Fibrosis Is Associated with a Defect in Apical Receptor–Mediated Endocytosis in Mouse and Human Kidney

Cystic Fibrosis Is Associated with a Defect in Apical Receptor–Mediated Endocytosis in Mouse and Human Kidney

Expression of the Voltage-Gated Sodium Channel NaV1.5 in the Macrophage Late Endosome Regulates Endosomal Acidification

Myosin VI Regulates Endocytosis of the Cystic Fibrosis Transmembrane Conductance Regulator

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