FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2906450229> ?p ?o ?g. }

• W2906450229 abstract "News & Views20 December 2018free access CFTR is not a gluten lover either Laura Vachel Epithelial Signaling and Transport Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA Search for more papers by this author Shmuel Muallem [email protected] orcid.org/0000-0002-6189-4947 Epithelial Signaling and Transport Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA Search for more papers by this author Laura Vachel Epithelial Signaling and Transport Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA Search for more papers by this author Shmuel Muallem [email protected] orcid.org/0000-0002-6189-4947 Epithelial Signaling and Transport Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA Search for more papers by this author Author Information Laura Vachel1 and Shmuel Muallem1 1Epithelial Signaling and Transport Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA EMBO J (2019)38:e101200https://doi.org/10.15252/embj.2018101200 See also: VR Villella et al (January 2019) PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Coeliac disease (CD) is an inflammatory autoimmune disease caused by ingestion of gluten proteins, mainly gliadin. Undigested gliadin proline-rich peptides trigger the innate and adaptive immune response, resulting in intestinal cell stress and damage. A new study by Villella et al (2019) addressing the unclear primary cause of intestinal cell stress reports that gliadin peptides inhibit the function of the chloride and bicarbonate channel CFTR, causing intestinal cell stress, which is sufficient to trigger CD symptoms. Notably, CFTR potentiators used to treat cystic fibrosis effectively rescue CFTR function and markedly ameliorate the pathology of coeliac disease. Coeliac disease (CD) is an inflammatory autoimmune disease affecting primarily the small intestine. The disease is common, with a prevalence of about 1 in 100, and affects individuals who express antigens HLA-DQ2 or HLA-DQ8 (Stamnaes & Sollid, 2015). CD is caused by oral intolerance to gluten, a group of storage proteins found in wheat, rye and barley. A key component of the gluten proteome is gliadin, which triggers a massive immune response that is exacerbated by stressed and damaged intestinal epithelial tissue. Gliadin contains proline-rich stretches that are resistant to proteolytic degradation by intestinal proteases and are transported to the lamina propria by transcytosis after deamidated by transglutaminase 2 (TG2; Stamnaes & Sollid, 2015). In the lamina propria, deamidated gliadin peptides activate the adaptive immune response, including pathogenic CD4+ T cell that produces large amounts of IFN (interferon)-γ and IL (interleukin)-21 and highly disease-specific B-cell responses that generate IgA against TG2 (Stamnaes & Sollid, 2015). The adaptive immune response causes epithelial cell stress, which promotes recruitment of invariant natural killer T (NKT) cells to the intestinal epithelium; this is believed to be a major driver of tissue destruction in CD. Here, Villella et al (2019) discovered a new likely key cause of intestinal cell stress and destruction due to inhibition of CFTR expression and function by gliadin peptides. Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated Cl− and conducting channel expressed in all secretory and absorptive epithelia, mutations in which cause cystic fibrosis (CF; Lee et al, 2012; Cutting, 2015). CFTR is a member of the ABC family of transporters: it has two transmembrane domains TMD1 and TMD2, two nucleotide-binding domains NBD1 and NBD2 and a regulatory domain (RD; Fig 1). CFTR plays an essential role in epithelial fluid and electrolyte transport and determines the final concentration in all secreted biological fluids (Lee et al, 2012). CFTR is the main pathway for intestinal Cl− secretion, supports luminal membrane Cl−/ exchange by Slc26a6 (Seidler, 2013), activates Slc26a3 and Slc26a6 (Ko et al, 2002) and secretes when luminal Cl− is low (Lee et al, 2012). In the absence of CFTR activity, fluid and secretion is markedly inhibited, leading to GI tissues severe cell stress, inflammation and cell death (Chen et al, 2018). The most common CF-causing mutation in CFTR is the deletion of phenylalanine 508 (ΔF508) in NBD1, which results in misfolding of CFTR and its degradation in the proteasome. The second most common mutations inhibit the channel function of CFTR without affecting synthesis or trafficking of the protein (Cutting, 2015). The FDA-approved small molecule CFTR potentiator VX-770 (Ivacaftor) is in use to treat patients with CFTR mutations that inhibit channel activity, whereas patients with the ΔF508 mutation are treated with a combination of VX-770 and the CFTR corrector VX-809 (lumacaftor), which increases targeting and expression of CFTR in the luminal membrane (Cutting, 2015). Figure 1. Interaction of the gliadin peptide P31-43 and VX-770 with CFTRThe 3D cryo-EM structure of human CFTR is shown in the inactive state (PDB 5UAK) on the left and in the active state (PDB 5W81) on the right. The CFTR structure is composed of transmembrane domain 1 (TMD1), nucleotide-binding domain 1 (NBD1), the R domain (not shown in the structure), transmembrane domain 2 (TMD2) and nucleotide-binding domain 2 (NBD2). The gliadin peptide P31-43 binds to NBD1 in the boundary between NBD1 and TMD1 to stabilize the inactive conformation of CFTR, in which NBD1 and NBD2 do not interact to form the ATP-binding site. VX-770 interacts with intracellular loop 4 that is close to the interaction site of P31-43 to prevent binding of P31-43 and stabilize the active conformation of CFTR, in which NBD1 and NBD2 interact to form the ATP-binding site and CFTR conducts Cl− and . Download figure Download PowerPoint Based on several similar intestinal symptoms in CD and CF, Villella et al (2019) reasoned that aberrant intestinal CFTR function might occur in CD, and if it does, it might be corrected by CFTR potentiators. Indeed, Villella et al found that gliadin administration triggers inflammatory response in CFTR−/− mice. Moreover, using gliadin to induce CD in WT mice markedly reduced CFTR expression and function, as well as reducing expression of the PDZ domains containing scaffolding protein NHERF1. Notably, aberrant intestinal barrier, intestinal expression of TG2, generation of anti-TG2 antibodies causing immunopathology and inflammation were all prevented by treating the mice with VX-770 while inducing the disease by administering gliadin. To probe the mechanism by which gliadin affects CFTR function, Villella et al examine the effects of the proteolysis-resistant, proline-rich gliadin-derived peptide P31-43 (Stamnaes & Sollid, 2015) on intestinal cells. P31-43 inhibited CFTR current by interacting with NBD1 in the boundary between NBD1 and TMD1, possibly by inducing the inactive conformation of CFTR by preventing interaction between NBD1 and NBD2 (Fig 1, left). VX-770 prevented the inhibition of CFTR by P31-43. Interestingly, recent findings indicate that VX-770 interacts with the CFTR surface formed by intracellular loop 4 (Byrnes et al, 2018), which is near the binding site of P31-43 (Fig 1, right). This suggests competition between P31-43 and VX-770 (Fig 1). In this respect, VX-770 cannot activate CFTR that is already bound with P31-43 and P31-43 cannot inhibit CFTR that is already bound with VX-770 (Villella et al (2019). By inhibiting the effects of P31-43, VX-770 prevented degradation of CFTR and of NHERF1, endosomal trafficking and the pathology observed in the intestinal Caco-2 cell line treated with P31-42. Rescuing NHERF1 not only stabilizes the cytoskeleton in the intestinal villi, but also allows CFTR to interact with and activate the luminal Cl−/ exchangers Slc26a6 and Slc26a3 by mediating their assembly into complexes (Ko et al, 2002). To verify the clinical significance of their findings in cell lines and mouse models, Villella et al (2019) used two models to examine the effect of VX-770 on gliadin-induced immune response in CD patients. Peripheral blood mononuclear cells (PBMCs) from CD patients in co-culture with Caco-2 were induced by gliadin peptides to produce IFN-γ, which was prevented by VX-770. Duodenal biopsies from CD patients challenged with gliadin peptides increased the number of CD3+CD25+ cells, an effect prevented by the CFTR potentiator Vrx-532. The overall findings of Villella et al (2019) suggest that CFTR potentiators may be used to reduce pathogenic inflammation in patients with CD, particularly the 20% of patients who are refractory to gluten-free diet (Lebwohl et al, 2018). The findings of Villella et al (2019) raise several questions. What is the mechanism by which rescuing CFTR resolves the immune and inflammatory responses? Does this involve washout of inflammatory mediators from the intestinal parenchyma and tissue repair? Can VX-770 reverse CD pathology and intestinal damage after their induction? CF patients with mutations that affect CFTR expression are treated with a combination of CFTR correctors and potentiators. In this respect, it is of interest that CFTR correctors and potentiators not only prevented, but also effectively reversed the damage and disease symptoms in mouse models of the autoimmune diseases Sjögren's syndrome and autoimmune pancreatitis (Zeng et al, 2017). In these disease models, CFTR is degraded, and while VX-770 reduced inflammation and tissue damage, the CFTR corrector C18 was more effective in restoring CFTR expression and tissue repair, including that of acinar cells that do not express CFTR (Zeng et al, 2017). It should be informative to test CFTR correctors alone and in combination with potentiators in CD. Finally, the findings of Villella et al (2019) and Zeng et al (2017) suggest that repurposing CFTR correctors and potentiators should be considered for treatment of other autoimmune diseases with gastrointestinal manifestations including inflammation and cell stress (Nay et al, 2015). References Byrnes LJ, Xu Y, Qiu X, Hall JD, West GM (2018) Sites associated with Kalydeco binding on human Cystic Fibrosis Transmembrane Conductance Regulator revealed by Hydrogen/Deuterium Exchange. Sci Rep 8: 4664CrossrefPubMedWeb of Science®Google Scholar Chen AC, Burr L, McGuckin MA (2018) Oxidative and endoplasmic reticulum stress in respiratory disease. Clin Transl Immunology 7: e1019Wiley Online LibraryPubMedWeb of Science®Google Scholar Cutting GR (2015) Cystic fibrosis genetics: from molecular understanding to clinical application. Nat Rev Genet 16: 45–56CrossrefCASPubMedWeb of Science®Google Scholar Ko SB, Shcheynikov N, Choi JY, Luo X, Ishibashi K, Thomas PJ, Kim JY, Kim KH, Lee MG, Naruse S, Muallem S (2002) A molecular mechanism for aberrant CFTR-dependent HCO(3)(-) transport in cystic fibrosis. EMBO J 21: 5662–5672Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Lebwohl B, Sanders DS, Green PHR (2018) Coeliac disease. Lancet 391: 70–81CrossrefPubMedWeb of Science®Google Scholar Lee MG, Ohana E, Park HW, Yang D, Muallem S (2012) Molecular mechanism of pancreatic and salivary gland fluid and HCO3 secretion. Physiol Rev 92: 39–74CrossrefCASPubMedWeb of Science®Google Scholar Nay J, Menias CO, Mellnick VM, Balfe DM (2015) Gastrointestinal manifestations of systemic disease: a multimodality review. Abdom Imaging 40: 1926–1943CrossrefPubMedGoogle Scholar Seidler UE (2013) Gastrointestinal HCO3- transport and epithelial protection in the gut: new techniques, transport pathways and regulatory pathways. Curr Opin Pharmacol 13: 900–908CrossrefCASPubMedWeb of Science®Google Scholar Stamnaes J, Sollid LM (2015) Celiac disease: autoimmunity in response to food antigen. Semin Immunol 27: 343–352CrossrefCASPubMedWeb of Science®Google Scholar Villella V, Venerando A, Cozza G, Esposito S, Ferrari E, Monzani R, Spinella M, Oikonomou V, Renga G, Tosco A, Rossin F, Guido S, Silano M, Garaci E, Chao YK, Grimm C, Luciani A, Romani L, Piacentini M, Raia V et al (2019) A pathogenic role for cystic fibrosis transmembrane conductance regulator in celiac disease. EMBO J 38: e100101Wiley Online LibraryPubMedWeb of Science®Google Scholar Zeng M, Szymczak M, Ahuja M, Zheng C, Yin H, Swaim W, Chiorini JA, Bridges RJ, Muallem S (2017) Restoration of CFTR activity in ducts rescues acinar cell function and reduces inflammation in pancreatic and salivary glands of mice. Gastroenterology 153: 1148–1159CrossrefCASPubMedWeb of Science®Google Scholar Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 38,Issue 2,15 January 2019Caption: E3 ubiquitin ligase Parkin (cyan) ubiquitinates the apoptotic effector protein BAK (purple) on the surface of damaged mitochondria to impair its apoptotic activity and inhibit cell death. Mutant forms of Parkin that cause early onset Parkinson's disease cannot ubiquitinate BAK. By Jonathan Bernardini, Grant Dewson and colleagues: Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy. Scientific image by Jonathan Bernardini, Grant Dewson, Vanessa Solomon, Simon Taplin, Etsuko Uno (Walter and Eliza Hall Institute). Volume 38Issue 215 January 2019In this issue FiguresReferencesRelatedDetailsLoading ..." @default.
• W2906450229 created "2019-01-01" @default.
• W2906450229 creator A5041743130 @default.
• W2906450229 creator A5068367436 @default.
• W2906450229 date "2018-12-20" @default.
• W2906450229 modified "2023-10-12" @default.
• W2906450229 title "CFTR is not a gluten lover either" @default.
• W2906450229 cites W1988185561 @default.
• W2906450229 cites W2071737041 @default.
• W2906450229 cites W2086293424 @default.
• W2906450229 cites W2113193681 @default.
• W2906450229 cites W2169500993 @default.
• W2906450229 cites W2173547288 @default.
• W2906450229 cites W2765407986 @default.
• W2906450229 cites W2807364537 @default.
• W2906450229 cites W2808647094 @default.
• W2906450229 cites W2902606683 @default.
• W2906450229 cites W4211144941 @default.
• W2906450229 doi "https://doi.org/10.15252/embj.2018101200" @default.
• W2906450229 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6331715" @default.
• W2906450229 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30573671" @default.
• W2906450229 hasPublicationYear "2018" @default.
• W2906450229 type Work @default.
• W2906450229 sameAs 2906450229 @default.
• W2906450229 citedByCount "0" @default.
• W2906450229 crossrefType "journal-article" @default.
• W2906450229 hasAuthorship W2906450229A5041743130 @default.
• W2906450229 hasAuthorship W2906450229A5068367436 @default.
• W2906450229 hasBestOaLocation W29064502291 @default.
• W2906450229 hasConcept C2776336767 @default.
• W2906450229 hasConcept C54355233 @default.
• W2906450229 hasConcept C55493867 @default.
• W2906450229 hasConcept C70721500 @default.
• W2906450229 hasConcept C86803240 @default.
• W2906450229 hasConceptScore W2906450229C2776336767 @default.
• W2906450229 hasConceptScore W2906450229C54355233 @default.
• W2906450229 hasConceptScore W2906450229C55493867 @default.
• W2906450229 hasConceptScore W2906450229C70721500 @default.
• W2906450229 hasConceptScore W2906450229C86803240 @default.
• W2906450229 hasIssue "2" @default.
• W2906450229 hasLocation W29064502291 @default.
• W2906450229 hasLocation W29064502292 @default.
• W2906450229 hasLocation W29064502293 @default.
• W2906450229 hasLocation W29064502294 @default.
• W2906450229 hasOpenAccess W2906450229 @default.
• W2906450229 hasPrimaryLocation W29064502291 @default.
• W2906450229 hasRelatedWork W1828691184 @default.
• W2906450229 hasRelatedWork W1903732681 @default.
• W2906450229 hasRelatedWork W1991523530 @default.
• W2906450229 hasRelatedWork W2002128513 @default.
• W2906450229 hasRelatedWork W2020824267 @default.
• W2906450229 hasRelatedWork W2031436818 @default.
• W2906450229 hasRelatedWork W2057739827 @default.
• W2906450229 hasRelatedWork W2075354549 @default.
• W2906450229 hasRelatedWork W2119103177 @default.
• W2906450229 hasRelatedWork W2092874662 @default.
• W2906450229 hasVolume "38" @default.
• W2906450229 isParatext "false" @default.
• W2906450229 isRetracted "false" @default.
• W2906450229 magId "2906450229" @default.
• W2906450229 workType "article" @default.