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• W2072260520 abstract "Editorial FociCFTR and GM1 “gangl-ing” up to heal thy wound. Focus on “Reduced GM1 ganglioside in CFTR-deficient human airway cells results in decreased β1-integrin signaling and delayed wound repair”Jada C. Domingue, and Mrinalini C. RaoJada C. DomingueDepartment of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, and Mrinalini C. RaoDepartment of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IllinoisPublished Online:01 May 2014https://doi.org/10.1152/ajpcell.00075.2014This is the final version - click for previous versionMoreSectionsPDF (526 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat ever since its discovery in 1989, the cystic fibrosis transmembrane conductance regulator has proven time and again that its name as a regulator and moniker, CFTR, are fully justified. The pleiotropic effects of CFTR continue to ingratiate themselves into the intricacies of cell regulation. In a previous Editorial Focus, Kevin Kirk (5) highlighted a study [Schiller, Maniak, and O'Grady (7)] that demonstrated delayed wound healing in cystic fibrosis (CF) airways is indeed due to the absence of functional CFTR Cl− channels. Furthermore, lamellipodia at the leading edge of the wound were curtailed in CFTR-compromised (shRNA or CFTRinh-172 treated) cells. Roles for CFTR in osmotic changes and membrane depolarization at the leading edge lamellipodia and in alkalinization at the trailing edge were discussed (7). Subsequently, CFTR was implicated in wound-induced electrical potentials (8). Although attractive and plausible, are these mechanisms sufficient to explain how the CFTR channel activity gets translated into cell migration and wound healing?Recently, Itokazu and colleagues (4; O'Grady is a collaborating author) have come closer to answering this question by demonstrating the role of an additional, perhaps primary, mechanism by which CFTR could act to modulate wound healing in airway cells. Using the same Calu-3 airway cell model and electrical cell impedance sensing (ECIS) to measure cell migration, the authors have elegantly shown that a missing link may be a cascade of events leading from GM1 gangliosides to β1-integrin and FAK/CAS signaling and hence wound healing (Fig. 1). What is their compelling evidence? Silencing of CFTR with shRNA dramatically reduces GM1 gangliosides and delays wound healing. Furthermore, treatment with CFTRinh-172 in CFTR-expressing cells, earlier shown to act much like CFTR-shRNA (7), also reduces GM1 ganglioside content, suggesting that the presence and activity of CFTR influences GM1 levels. The depletion is neither due to the lack of substrate, ceramide, nor to a decrease in the activity of glucosylceramide synthase, which modulates the first step in GM1 biosynthesis from ceramide. Nor was ceramide being routed into sphingomyelin as there was no change in sphingomyelin synthase activity (4). These authors did not measure all the steps of the ganglioside synthetic pathway although others have shown that the absence of CFTR affects terminal glycosylation (sialylation) of GM1 as well as of a number of proteins (6). However, there is an increase in GM1 degradation in the CFTR-shRNA cells, and although significant, it is only a 20% increase and does not fully account for the overall ≈60% decrease in GM1 content. Replenishment of GM1, but not GM3, restored the rate of wound healing in CFTR-shRNA cells (4).Fig. 1.CFTR and GM1 “gangl-ing” up: a new role for CFTR in airway wound healing. Events at the airway epithelial cell edge in response to wounding are depicted in CFTR-silenced and CFTR-replete cells. A: CFTR-silenced cell. In cells where CFTR activity has been silenced either by shRNA (shown) or by CFTRinh-172 (not shown), there is a decrease in membrane GM1 ganglioside (blue triangle doublets) and a decrease in activated β1-integrin and its downstream signaling cascade of FAK, CAS, and actin. Low GM1 levels may be due to a decrease in terminal glycosylation (single triangles) and/or an increase in GM1 degradation in lysosomes. In the absence of CFTR, the trafficking of vesicles may be impaired by undocked SNARE proteins (yellow arcs). B: CFTR-replete cell. The cells respond by lamellipodial extensions, and GM1 gangliosides activate β1-integrin signaling with an increase in phosphorylation of FAK, CAS, and recruitment of actin. CFTR activity alters pH in intracellular compartments and contributes to wound-induced changes in plasma membrane potential. In the presence of CFTR, trafficking of vesicles with properly docked SNARE proteins occurs (yellow stars).Download figureDownload PowerPointGangliosides, including GM1, contribute to the microdomains and lipid rafts that help cluster β1-integrin in the membrane (4). This clustering is critical for distal signaling steps, including the recruitment and activation of FAK and its subsequent recruitment of CAS and microfilaments, which are necessary for lamellipodial extension and wound healing. In the absence of CFTR in Calu-3 cells, while there is no change in the amount of β1-integrin, these proteins fail to be activated and do not appear to cluster in microdomains (Fig. 1A). Refurbishing GM1 is sufficient to “restore” β1-integrin clustering into microdomains and appears to be sufficient to restore the activation of FAK and CAS (4). An emerging picture of wound healing in airway cells is as follows: the cells move as a sheet with β1-integrins and actin being essential, and CFTR activity promotes migration by ensuring adequate GM1 levels, and by alterations in ionic balance (osmotic, membrane potential, alkalinization) at the lamellipodia (Fig. 1B) (4, 5, 7, 8).Like all good science, these studies generate more questions. Clearly, the restitution of wound healing by restoring GM1 gangliosides to control levels is not 100%. Why does refurbishment of GM1 not fully recover the wound healing response? While GM3 had no effect, are there other gangliosides or membrane lipids needed for complete restitution? If so, is it through similar or different mechanisms? Are the decreases in lamellipodia (7) in CFTR-silenced cells due to the lack of GM1 alone? Most likely the CFTR-dependent decrease in GM1 is due to alterations in pH in various intracellular compartments, resulting in a 20% increase in degradation (lysosomes) and a decrease in the terminal sialylation (Golgi and endosomal vesicles) in GM1 synthesis, while the early steps of GM1 biosynthesis are not affected (Fig. 1A). The remaining 40% of GM1 in CFTR-depleted cells is insufficient, raising the question of whether there is compartmentalization of GM1. It is nevertheless apparent that wound healing involves CFTR regulation of GM1 ganglioside levels.It is important to recognize that CFTR plays a modulatory role, since in the absence of CFTR activity and protein, wound closure occurs, albeit requiring three times as long to achieve. What are the salvage pathways that allow this to occur and are they a potential therapeutic site for augmenting wound healing? While CFTRinh-172 studies suggest that CFTR activity is essential, it is not clear whether the entire wound healing response is dependent on CFTR function. Aside from its activity, CFTR also serves as a docking protein in different intracellular compartments, inviting protein-protein interactions with a variety of signaling molecules, such as SNAREs (9). In addition to GM1, does the absence of CFTR prevent proper trafficking of other proteins involved in wound healing to their target membrane destination?Does CFTR play a similar role in wound healing in other exocrine tissues, in particular the intestine? The intestine is subject to daily assault of its luminal surface, and many mechanisms help cope with this including its tightly programmed 4–5 day epithelial turnover along the crypt-villus axis, resulting in villus tip enterocyte extrusion (1). Finally, is there a physiological advantage to a depletion of GM1 in the intestine? After all, GM1 is the receptor for cholera toxin (10) and there have been conflicting reports that CF may protect from susceptibility to cholera (2, 3). Is part of this protection a decrease in the receptor that recognizes the toxin?There are other cellular processes that will probably “gang” up with CFTR in wound healing. Perhaps it is time we coined “CFTRome” to underscore the multiple influences of this protein.GRANTSThis work was supported by an institutional (University of Illinois) grant (to M. C. Rao).DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the author(s).AUTHOR CONTRIBUTIONSJ.C.D. and M.C.R. prepared figure; drafted manuscript; edited and revised manuscript; approved final version of manuscript.REFERENCES1. Eisenhoffer GT, Loftus PD, Yoshigi M, Otsuna H, Chien CB, Morcos PA, Rosenblatt J. Crowding induces live cell extrusion to maintain homeostatic cell numbers in epithelia. Nature 484: 546–549, 2012.Crossref | PubMed | ISI | Google Scholar2. Gabriel SE, Brigman KN, Koller BH, Boucher RC, Stutts MJ. Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model. Science 266: 107–109, 1994.Crossref | PubMed | ISI | Google Scholar3. Hogenauer C, Santa Ana CA, Porter JL, Millard M, Gelfand A, Rosenblatt RL, Prestidge CB, Fordtran JS. Active intestinal chloride secretion in human carriers of cystic fibrosis mutations: an evaluation of the hypothesis that heterozygotes have subnormal active intestinal chloride secretion. Am J Hum Genet 67: 1422–1427, 2000.Crossref | PubMed | ISI | Google Scholar4. Itokazu Y, Pagano RE, Schroeder AS, O'Grady SM, Limper AH, Marks DL. Reduced GM1 ganglioside in CFTR-deficient human airway cells results in decreased β1-integrin signaling and delayed wound repair. Am J Physiol Cell Physiol (February 5, 2014). doi:10.1152/ajpcell.00168.2013.Link | ISI | Google Scholar5. Kirk KL. CFTR channels and wound healing. Focus on “Cystic fibrosis transmembrane conductance regulator is involved in airway epithelial wound repair.” Am J Physiol Cell Physiol 299: C888–C890, 2010.Link | ISI | Google Scholar6. Rhim AD, Stoykova LI, Trindade AJ, Glick MC, Scanlin TF. Altered terminal glycosylation and the pathophysiology of CF lung disease. J Cyst Fibros 3, Suppl 2: 95–96, 2004.Crossref | PubMed | Google Scholar7. Schiller KR, Maniak PJ, O'Grady SM. Cystic fibrosis transmembrane conductance regulator is involved in airway epithelial wound repair. Am J Physiol Cell Physiol 299: C912–C921, 2010.Link | ISI | Google Scholar8. Sun YH, Reid B, Fontaine JH, Miller LA, Hyde DM, Mogilner A, Zhao M. Airway epithelial wounds in rhesus monkey generate ionic currents that guide cell migration to promote healing. J Appl Physiol 111: 1031–1041, 2011.Link | ISI | Google Scholar9. Tang BL, Gee HY, Lee MG. The cystic fibrosis transmembrane conductance regulator's expanding SNARE interactome. Traffic 12: 364–371, 2011.Crossref | PubMed | ISI | Google Scholar10. Wernick NL, Chinnapen DJ, Cho JA, Lencer WI. Cholera toxin: an intracellular journey into the cytosol by way of the endoplasmic reticulum. Toxins (Basel) 2: 310–325, 2010.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: M. C. Rao, Dept. of Physiology and Biophysics, Univ. of Illinois at Chicago, 835 South Wolcott, m/c 901, Chicago IL 60612-7342 (e-mail: [email protected]edu). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByPhysiology of Electrolyte Transport in the Gut: Implications for Disease12 June 2019CFTR Involvement in Cell Migration and Epithelial Restitution12 July 2017Lithocholic acid attenuates cAMP-dependent Cl− secretion in human colonic epithelial T84 cellsMei Ao, Jada C. Domingue, Nabihah Khan, Fatima Javed, Kashif Osmani, Jayashree Sarathy, and Mrinalini C. Rao15 June 2016 | American Journal of Physiology-Cell Physiology, Vol. 310, No. 11Reduced GM1 ganglioside in CFTR-deficient human airway cells results in decreased β1-integrin signaling and delayed wound repairYutaka Itokazu, Richard E. Pagano†, Andreas S. Schroeder, Scott M. O'Grady, Andrew H. Limper, and David L. Marks1 May 2014 | American Journal of Physiology-Cell Physiology, Vol. 306, No. 9 More from this issue > Volume 306Issue 9May 2014Pages C789-C791 Copyright & PermissionsCopyright © 2014 the American Physiological Societyhttps://doi.org/10.1152/ajpcell.00075.2014PubMed24627559History Published online 1 May 2014 Published in print 1 May 2014 Metrics" @default.
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