title: A novel regulatory role for tissue transglutaminase in epithelial-mesenchymal transition in cystic fibrosis.
abstract: Cystic fibrosis (CF) is a genetic disorder caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) for which there is no overall effective treatment. Recent work indicates tissue transglutaminase (TG2) plays a pivotal intracellular role in proteostasis in CF epithelia and that the pan TG inhibitor cysteamine improves CFTR stability. Here we show TG2 has another role in CF pathology linked with TGFβ1 activation and signalling, induction of epithelial-mesenchymal transition (EMT), CFTR stability and induction of matrix deposition. We show that increased TG2 expression in normal and CF bronchial epithelial cells increases TGFβ1 levels, promoting EMT progression, and impairs tight junctions as measured by Transepithelial Electric Resistance (TEER) which can be reversed by selective inhibition of TG2 with an observed increase in CFTR stability. Our data indicate that selective inhibition of TG2 provides a potential therapeutic avenue for reducing fibrosis and increasing CFTR stability in CF.
authors.affiliation: School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, United Kingdom.
authors.forename: Samuel
authors.initials: S
authors.lastname: Nyabam
authors.affiliation: School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, United Kingdom. Electronic address: wangz8@aston.ac.uk.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Thibault
authors.affiliation: School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, United Kingdom.
authors.forename: Ayinde
authors.initials: A
authors.lastname: Oluseyi
authors.affiliation: School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, United Kingdom.
authors.forename: Rameeza
authors.initials: R
authors.lastname: Basar
authors.affiliation: School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, United Kingdom.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Marshall
authors.affiliation: School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, United Kingdom. Electronic address: m.griffin@aston.ac.uk.
authors.forename: Martin
authors.initials: M
authors.lastname: Griffin
mesh_terms: D000388:Air; D015415:Biomarkers / Q000378:metabolism; D019921:Biotinylation / Q000187:drug effects; D001980:Bronchi / Q000473:pathology; D002460:Cell Line; D003550:Cystic Fibrosis / Q000201:enzymology* / Q000473:pathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D017097:Electric Impedance; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D050505:Mutant Proteins / Q000378:metabolism; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D034741:RNA, Small Interfering / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D011503:Transglutaminases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D050505:Mutant Proteins; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: Cystic fibrosis; Cystic fibrosis transmembrane conductance regulator; Epithelial-mesenchymal transition; Tissue transglutaminase; Transforming growth factor β