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Loss of MYO5B Leads to Reductions in Na Absorption With Maintenance of CFTR-Dependent Cl Secretion in Enterocytes.
Engevik AC, Kaji I, Engevik MA, Meyer AR, Weis VG, Goldstein A, Hess MW, Müller T, Koepsell H, Dudeja PK, Tyska M, Huber LA, Shub MD, Ameen N, Goldenring JR
(2018) Gastroenterology 155: 1883-1897.e10
MeSH Terms: Animals, Aquaporins, Chlorides, Cystic Fibrosis Transmembrane Conductance Regulator, Duodenum, Enterocytes, Gene Silencing, Humans, Intestinal Mucosa, Intestines, Malabsorption Syndromes, Mice, Mice, Knockout, Microvilli, Mucolipidoses, Myosin Type V, Protein Transport, Sodium-Glucose Transporter 1, Sodium-Hydrogen Exchanger 3, Sodium-Hydrogen Exchangers, Sucrase-Isomaltase Complex, Tamoxifen
Show Abstract · Added February 7, 2019
BACKGROUND & AIMS - Inactivating mutations in MYO5B cause microvillus inclusion disease (MVID), but the physiological cause of the diarrhea associated with this disease is unclear. We investigated whether loss of MYO5B results in aberrant expression of apical enterocyte transporters.
METHODS - We studied alterations in apical membrane transporters in MYO5B-knockout mice, as well as mice with tamoxifen-inducible, intestine-specific disruption of Myo5b (VilCre;Myo5b mice) or those not given tamoxifen (controls). Intestinal tissues were collected from mice and analyzed by immunostaining, immunoelectron microscopy, or cultured enteroids were derived. Functions of brush border transporters in intestinal mucosa were measured in Ussing chambers. We obtained duodenal biopsy specimens from individuals with MVID and individuals without MVID (controls) and compared transporter distribution by immunocytochemistry.
RESULTS - Compared to intestinal tissues from littermate controls, intestinal tissues from MYO5B-knockout mice had decreased apical localization of SLC9A3 (also called NHE3), SLC5A1 (also called SGLT1), aquaporin (AQP) 7, and sucrase isomaltase, and subapical localization of intestinal alkaline phosphatase and CDC42. However, CFTR was present on apical membranes of enterocytes from MYO5B knockout and control mice. Intestinal biopsies from patients with MVID had subapical localization of NHE3, SGLT1, and AQP7, but maintained apical CFTR. After tamoxifen administration, VilCre;Myo5b mice lost apical NHE3, SGLT1, DRA, and AQP7, similar to germline MYO5B knockout mice. Intestinal tissues from VilCre;Myo5b mice had increased CFTR in crypts and CFTR localized to the apical membranes of enterocytes. Intestinal mucosa from VilCre;Myo5b mice given tamoxifen did not have an intestinal barrier defect, based on Ussing chamber analysis, but did have decreased SGLT1 activity and increased CFTR activity.
CONCLUSIONS - Although trafficking of many apical transporters is regulated by MYO5B, trafficking of CFTR is largely independent of MYO5B. Decreased apical localization of NHE3, SGLT1, DRA, and AQP7 might be responsible for dysfunctional water absorption in enterocytes of patients with MVID. Maintenance of apical CFTR might exacerbate water loss by active secretion of chloride into the intestinal lumen.
Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.
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MeSH Terms
Trafficking Ion Transporters to the Apical Membrane of Polarized Intestinal Enterocytes.
Engevik AC, Goldenring JR
(2018) Cold Spring Harb Perspect Biol 10:
MeSH Terms: Animals, Cell Membrane, Cell Polarity, Cystic Fibrosis Transmembrane Conductance Regulator, Cytoskeletal Proteins, Enterocytes, Humans, Ion Transport, Malabsorption Syndromes, Membrane Transport Proteins, Microvilli, Mucolipidoses, Myosin Heavy Chains, Myosin Type V, Protein Transport, Sodium-Hydrogen Exchanger 3
Show Abstract · Added April 18, 2017
Epithelial cells lining the gastrointestinal tract require distinct apical and basolateral domains to function properly. Trafficking and insertion of enzymes and transporters into the apical brush border of intestinal epithelial cells is essential for effective digestion and absorption of nutrients. Specific critical ion transporters are delivered to the apical brush border to facilitate fluid and electrolyte uptake. Maintenance of these apical transporters requires both targeted delivery and regulated membrane recycling. Examination of altered apical trafficking in patients with Microvillus Inclusion disease caused by inactivating mutations in MYO5B has led to insights into the regulation of apical trafficking by elements of the apical recycling system. Modeling of MYO5B loss in cell culture and animal models has led to recognition of Rab11a and Rab8a as critical regulators of apical brush border function. All of these studies show the importance of apical membrane trafficking dynamics in maintenance of polarized epithelial cell function.
Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.
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16 MeSH Terms
Influence of Pathogenic Mutations on the Energetics of Translocon-Mediated Bilayer Integration of Transmembrane Helices.
Schlebach JP, Sanders CR
(2015) J Membr Biol 248: 371-81
MeSH Terms: Amino Acid Sequence, Animals, Cattle, Conserved Sequence, Cystic Fibrosis Transmembrane Conductance Regulator, Humans, KCNQ1 Potassium Channel, Lipid Bilayers, Mutation, Mutation, Missense, Myelin Proteins, Protein Structure, Secondary, Protein Transport, Receptors, Vasopressin, Rhodopsin, Thermodynamics
Show Abstract · Added November 21, 2018
Aberrant protein folding and assembly contribute to a number of diseases, and efforts to rationalize how pathogenic mutations cause this phenomenon represent an important imperative in biochemical research. However, for α-helical membrane proteins, this task is complicated by the fact that membrane proteins require intricate machinery to achieve structural and functional maturity under cellular conditions. In this work, we utilized the ΔG predictor algorithm ( www.dgpred.cbr.su.se ) to survey 470 known pathogenic mutations occurring in five misfolding-prone α-helical membrane proteins for their predicted effects on the translocon-mediated membrane integration of transmembrane helices, a critical step in biosynthesis and folding of nascent membrane proteins. The results suggest that about 10 % of these mutations are likely to have adverse effects on the topogenesis of nascent membrane proteins. These results suggest that the misfolding of a modest but nonetheless significant subset of pathogenic variants may begin at the translocon. Potential implications for therapeutic design and personalized medicine are discussed.
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Macrophages promote progression of spasmolytic polypeptide-expressing metaplasia after acute loss of parietal cells.
Petersen CP, Weis VG, Nam KT, Sousa JF, Fingleton B, Goldenring JR
(2014) Gastroenterology 146: 1727-38.e8
MeSH Terms: Adaptive Immunity, Animals, Atrophy, Cell Proliferation, Cell Transformation, Neoplastic, Cystic Fibrosis Transmembrane Conductance Regulator, Disease Models, Animal, Gastritis, Gene Expression Regulation, Neoplastic, Glutathione Peroxidase, Homeodomain Proteins, Immunity, Innate, Inflammation Mediators, Interferon-gamma, Macrophages, Male, Metaplasia, Mice, Mice, Inbred C57BL, Mice, Knockout, Mucins, Neutrophils, Parietal Cells, Gastric, Peptides, Phenotype, RNA, Messenger, Stomach Neoplasms, Up-Regulation
Show Abstract · Added March 10, 2014
BACKGROUND & AIMS - Loss of parietal cells causes the development of spasmolytic polypeptide-expressing metaplasia (SPEM) through transdifferentiation of chief cells. In the presence of inflammation, SPEM can advance into a more proliferative metaplasia with increased expression of intestine-specific transcripts. We used L635 to induce acute SPEM with inflammation in mice and investigated the roles of inflammatory cells in the development of SPEM.
METHODS - To study the adaptive immune system, Rag1 knockout, interferon-γ-deficient, and wild-type (control) mice received L635 for 3 days. To study the innate immune system, macrophages were depleted by intraperitoneal injection of clodronate liposomes 2 days before and throughout L635 administration. Neutrophils were depleted by intraperitoneal injection of an antibody against Ly6G 2 days before and throughout L635 administration. Pathology and immunohistochemical analyses were used to determine depletion efficiency, metaplasia, and proliferation. To characterize SPEM in each model, gastric tissues were collected and levels of Cftr, Dmbt1, and Gpx2 mRNAs were measured. Markers of macrophage polarization were used to identify subpopulations of macrophages recruited to the gastric mucosa.
RESULTS - Administration of L635 to Rag1 knockout, interferon-γ-deficient, and neutrophil-depleted mice led to development of proliferative SPEM and up-regulation of intestine-specific transcripts in SPEM cells, similar to controls. However, macrophage-depleted mice given L635 showed significant reductions in numbers of SPEM cells, SPEM cell proliferation, and expression of intestine-specific transcripts, compared with control mice given L635. In mice given L635, as well as patients with intestinal metaplasia, M2 macrophages were the primary inflammatory component.
CONCLUSIONS - Results from studies of mouse models and human metaplastic tissues indicate that M2 macrophages promote the advancement of SPEM in the presence of inflammation.
Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.
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28 MeSH Terms
The mitochondrial complex I activity is reduced in cells with impaired cystic fibrosis transmembrane conductance regulator (CFTR) function.
Valdivieso AG, Clauzure M, Marín MC, Taminelli GL, Massip Copiz MM, Sánchez F, Schulman G, Teiber ML, Santa-Coloma TA
(2012) PLoS One 7: e48059
MeSH Terms: Animals, Cattle, Cell Line, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Electron Transport Complex I, Gene Knockdown Techniques, Humans, Mitochondria, Models, Biological, NADH Dehydrogenase, RNA Interference, RNA, Small Interfering
Show Abstract · Added February 26, 2014
Cystic fibrosis (CF) is a frequent and lethal autosomal recessive disease. It results from different possible mutations in the CFTR gene, which encodes the CFTR chloride channel. We have previously studied the differential expression of genes in CF and CF corrected cell lines, and found a reduced expression of MTND4 in CF cells. MTND4 is a mitochondrial gene encoding the MTND4 subunit of the mitochondrial Complex I (mCx-I). Since this subunit is essential for the assembly and activity of mCx-I, we have now studied whether the activity of this complex was also affected in CF cells. By using Blue Native-PAGE, the in-gel activity (IGA) of the mCx-I was found reduced in CFDE and IB3-1 cells (CF cell lines) compared with CFDE/6RepCFTR and S9 cells, respectively (CFDE and IB3-1 cells ectopically expressing wild-type CFTR). Moreover, colon carcinoma T84 and Caco-2 cells, which express wt-CFTR, either treated with CFTR inhibitors (glibenclamide, CFTR(inh)-172 or GlyH101) or transfected with a CFTR-specific shRNAi, showed a significant reduction on the IGA of mCx-I. The reduction of the mCx-I activity caused by CFTR inhibition under physiological or pathological conditions may have a profound impact on mitochondrial functions of CF and non-CF cells.
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Heterogeneity in mouse spasmolytic polypeptide-expressing metaplasia lineages identifies markers of metaplastic progression.
Weis VG, Sousa JF, LaFleur BJ, Nam KT, Weis JA, Finke PE, Ameen NA, Fox JG, Goldenring JR
(2013) Gut 62: 1270-9
MeSH Terms: Animals, Azetidines, Biomarkers, Clusterin, Cystic Fibrosis Transmembrane Conductance Regulator, Disease Models, Animal, Gene Expression Profiling, Gene Expression Regulation, Helicobacter Infections, Humans, Inflammation, Intestines, Laser Capture Microdissection, Metaplasia, Mice, Mice, Inbred CFTR, Parietal Cells, Gastric, Peptides, Piperazines, Precancerous Conditions, Up-Regulation
Show Abstract · Added October 7, 2013
OBJECTIVES - Spasmolytic polypeptide-expressing metaplasia (SPEM) develops as a preneoplastic lesion in the stomachs of mice and humans after parietal cell loss. To identify the commonalities and differences between phenotypic SPEM lineages, SPEM were studied from three different mouse models of parietal cell loss: with chronic inflammation with Helicobacter felis infection; with acute inflammation with L635 treatment; and without inflammation following DMP-777 treatment.
DESIGN - RNA transcripts from laser capture microdissected normal chief cells and SPEM lineages were compared using gene microarray. Alterations in transcripts were validated by quantitative real-time PCR. Clusterin and cystic fibrosis transmembrane conductance regulator (CFTR) were selected for immunohistochemical analysis in all mouse models as well as in human SPEM, intestinal metaplasia and gastric cancer.
RESULTS - Transcript expression patterns demonstrated differences among the phenotypic SPEM models. Clusterin expression was significantly upregulated in all three mouse SPEM models as well as in human SPEM. The highest clusterin expression in human gastric cancers correlated with poor survival. Conversely, CFTR expression was upregulated only in SPEM with inflammation in mice. In humans, intestinal metaplasia, but not SPEM, expressed CFTR.
CONCLUSIONS - While markers such as clusterin are expressed in all phenotypic SPEM lineages, distinct patterns of upregulated genes including CFTR are present in murine metaplasia associated with inflammation, indicative of progression of metaplasia towards a more intestinalised metaplastic phenotype.
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21 MeSH Terms
ERp29 regulates DeltaF508 and wild-type cystic fibrosis transmembrane conductance regulator (CFTR) trafficking to the plasma membrane in cystic fibrosis (CF) and non-CF epithelial cells.
Suaud L, Miller K, Alvey L, Yan W, Robay A, Kebler C, Kreindler JL, Guttentag S, Hubbard MJ, Rubenstein RC
(2011) J Biol Chem 286: 21239-53
MeSH Terms: Animals, Biotinylation, Cell Membrane, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Electrophysiology, Endoplasmic Reticulum, Epithelial Cells, Heat-Shock Proteins, Humans, Ions, Oocytes, Phenylbutyrates, Protein Transport, Xenopus
Show Abstract · Added January 20, 2015
Sodium 4-phenylbutyrate (4PBA) improves the intracellular trafficking of ΔF508-CFTR in cystic fibrosis (CF) epithelial cells. The underlying mechanism is uncertain, but 4PBA modulates the expression of some cytosolic molecular chaperones. To identify other 4PBA-regulated proteins that might regulate ΔF508-CFTR trafficking, we performed a differential display RT-PCR screen on IB3-1 CF bronchiolar epithelial cells exposed to 4PBA. One transcript up-regulated by 4PBA encoded ERp29, a luminal resident of the endoplasmic reticulum (ER) thought to be a novel molecular chaperone. We tested the hypothesis that ERp29 is a 4PBA-regulated ER chaperone that influences ΔF508-CFTR trafficking. ERp29 mRNA and protein expression was significantly increased (∼1.5-fold) in 4PBA-treated IB3-1 cells. In Xenopus oocytes, ERp29 overexpression increased the functional expression of both wild-type and ΔF508-CFTR over 3-fold and increased wild-type cystic fibrosis transmembrane conductance regulator (CFTR) plasma membrane expression. In CFBE41o- WT-CFTR cells, expression of and short circuit currents mediated by CFTR decreased upon depletion of ERp29 as did maturation of newly synthesized CFTR. In IB3-1 cells, ΔF508-CFTR co-immunoprecipitated with endogenous ERp29, and overexpression of ERp29 led to increased ΔF508-CFTR expression at the plasma membrane. These data suggest that ERp29 is a 4PBA-regulated ER chaperone that regulates WT-CFTR biogenesis and can promote ΔF508-CFTR trafficking in CF epithelial cells.
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15 MeSH Terms
Murine model for cystic fibrosis bone disease demonstrates osteopenia and sex-related differences in bone formation.
Pashuck TD, Franz SE, Altman MK, Wasserfall CH, Atkinson MA, Wronski TJ, Flotte TR, Stalvey MS
(2009) Pediatr Res 65: 311-6
MeSH Terms: Animals, Body Weights and Measures, Bone Diseases, Metabolic, Bone and Bones, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Disease Models, Animal, Female, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Osteogenesis, Sex Factors
Show Abstract · Added September 20, 2016
As the incidence of cystic fibrosis (CF) bone disease is increasing, we analyzed CF transmembrane conductance regulator (CFTR) deficient mice (CF mice) to gain pathogenic insights. In these studies comparing adult (14 wk) CF and C57BL/6J mice, both bone length and total area were decreased in CF mice. Metaphyseal trabecular and cortical density were also decreased, as well as diaphyseal cortical and total density. Trabecular bone volume was diminished in CF mice. Female CF mice revealed decreased trabecular width and number compared with C57BL/6J, whereas males demonstrated no difference in trabecular number. Female CF mice had reduced mineralizing surface and bone formation rates. Conversely, male CF mice had increased mineralizing surface, mineral apposition, and bone formation rates compared with C57BL/6J males. Bone formation rate was greater in males compared with female CF mice. Smaller bones with decreased density in CF, despite absent differences in osteoblast and osteoclast surfaces, suggest CF transmembrane conductance regulator influences bone cell activity rather than number. Differences in bone formation rate in CF mice are suggestive of inadequate bone formation in females but increased bone formation in males. This proanabolic observation in male CF mice is consistent with other clinical sex differences in CF.
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14 MeSH Terms
KGF alters gene expression in human airway epithelia: potential regulation of the inflammatory response.
Prince LS, Karp PH, Moninger TO, Welsh MJ
(2001) Physiol Genomics 6: 81-9
MeSH Terms: Active Transport, Cell Nucleus, Cell Division, Cells, Cultured, Chlorides, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, DNA-Binding Proteins, Fibroblast Growth Factor 7, Fibroblast Growth Factors, Gene Expression Profiling, Gene Expression Regulation, Humans, Inflammation, Interferons, Ion Transport, Kinetics, RNA, Messenger, Respiratory Mucosa, STAT1 Transcription Factor, Trans-Activators, Transcription, Genetic
Show Abstract · Added June 9, 2010
Keratinocyte growth factor (KGF) regulates several functions in adult and developing lung epithelia; it causes proliferation, stimulates secretion of fluid and electrolytes, enhances repair, and may minimize injury. To gain insight into the molecular processes influenced by KGF, we applied KGF to primary cultures of well-differentiated human airway epithelia and used microarray hybridization to assess the abundance of gene transcripts. Of 7,069 genes tested, KGF changed expression levels of 910. Earlier studies showed that KGF causes epithelial proliferation, and as expected, treatment altered expression of numerous genes involved in cell proliferation. We found that KGF stimulated transepithelial Cl(-) transport, but the number of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) transcripts fell. Although transcripts for ClC-1 and ClC-7 Cl(-) channels increased, KGF failed to augment transepithelial Cl(-) transport in CF epithelia, suggesting that KGF-stimulated Cl(-) transport in differentiated airway epithelia depends on the CFTR Cl(-) channel. Interestingly, KGF decreased transcripts for many interferon (IFN)-induced genes. IFN causes trafficking of Stat dimers to the nucleus, where they activate transcription of IFN-induced genes. We found that KGF prevented the IFN-stimulated trafficking of Stat1 from the cytosol to the nucleus, suggesting a molecular mechanism for KGF-mediated suppression of the IFN-signaling pathway. These results suggest that in addition to stimulating proliferation and repair of damaged airway epithelia, KGF stimulates Cl(-) transport and may dampen the response of epithelial cells to inflammatory mediators.
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21 MeSH Terms
Dysregulated cytokine production in human cystic fibrosis bronchial epithelial cells.
Stecenko AA, King G, Torii K, Breyer RM, Dworski R, Blackwell TS, Christman JW, Brigham KL
(2001) Inflammation 25: 145-55
MeSH Terms: Bronchi, Cells, Cultured, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Cytokines, Epithelial Cells, Humans, Inflammation, Inflammation Mediators, Interleukin-1, Interleukin-6, Interleukin-8, Tumor Necrosis Factor-alpha
Show Abstract · Added December 21, 2013
Although pulmonary inflammation is an important pathologic event in cystic fibrosis (CF), the relationship between expression of the CF gene and the inflammatory response is unclear. We studied tumor necrosis factor (TNF) alpha and IL-1beta stimulated production of IL-6 and IL-8 by CF, corrected CF, and normal human bronchial epithelial cells in culture. During the first 24 hours of TNFalpha stimulation, CF cells produced significantly more IL-8 than normal or corrected CF cells. In the second 24 hours of TNFalpha stimulation, IL-6 and IL-8 generation ceased in normal and corrected CF cells but accelerated in CF cells, resulting in marked IL-6 and IL-8 accumulation in CF cells. Similar results were found when cells were stimulated with IL-1beta. Finally, when CF cells were grown at 27 degrees C (a culture condition which results in transport of CF transmembrane conductance regulator, CFTR, to the cell membrane and normalization of chloride conductance) TNFalpha-stimulated production of IL-6 and IL-8 reverted to normal. We conclude that dysregulation of cytokine generation by CF bronchial epithelial cells is directly related to expression of mutant CFTR and these observations provide a potential mechanism for persistence of airway inflammation in CF.
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13 MeSH Terms