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.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bbamcr.2016.05.012 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Efficacy of Cystic Fibrosis Transmembrane Regulator Corrector C17 in Beta-Sarcoglycanopathy-Assessment of Patient's Primary Myotubes.
Int J Mol Sci
December 2024
Department of Biomedical Sciences, University of Padova, Via U. Bassi 58/B, 35131 Padova, Italy.
Limb-girdle muscular dystrophy type 2E/R4 (LGMD2E/R4) is a rare disease that currently has no cure. It is caused by defects in the gene, mainly missense mutations, which cause the impairment of the sarcoglycan complex, membrane fragility, and progressive muscle degeneration. Here, we studied the fate of some β-sarcoglycan (β-SG) missense mutants, confirming that, like α-SG missense mutants, they are targeted for degradation through the ubiquitin-proteasome system.
View Article and Find Full Text PDFSuccessful Therapy over 12 Months of People with Cystic Fibrosis with Rare Non-phe508del Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Mutations with Elexacaftor/Tezacaftor/Ivacaftor (ETI).
Adv Respir Med
December 2024
Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm University, 89075 Ulm, Germany.
Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a CFTR modulator therapy approved for people with cystic fibrosis (pwCF) who have at least one phe508del mutation. However, its approval in the European Union (EU) for pwCF with non-phe508del mutations is lacking, because data on treatment response in this subgroup are scarce. This retrospective observational study evaluated six pwCF (ages 6 to 66) with responsive CFTR mutations (M1101K, R347P, 2789+5G>A, G551D) undergoing off-label ETI therapy.
View Article and Find Full Text PDFCardiometabolic risk factors in adults with cystic fibrosis undergoing elexacaftor/tezacaftor/ivacaftor therapy.
J Cyst Fibros
December 2024
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Respiratory Unit and Cystic Fibrosis Adult Center, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Article Synopsis
- - The introduction of ETI therapy has improved life expectancy for adults with cystic fibrosis, but it raises concerns about long-term health issues, particularly cardiovascular risks due to existing factors linked to CF.
- - A study involving 58 adults with CF assessed changes in cardiac and metabolic biomarkers after 6 months on ETI therapy, revealing increased cholesterol and triglycerides levels while inflammatory markers decreased.
- - The findings indicate a disruption in hormone regulation related to obesity and cardiovascular risk, suggesting that while ETI improves some aspects of health, it negatively affects lipid profiles in patients, leading to potential metabolic issues.
Traditionally, the thermostability of a protein is defined by a melting temperature, at which half of the protein is unfolded. However, this definition cannot indicate the structural origin of a heat-induced unfolding pathway. Here, the thermoring structures were studied on the ATP-dependent heat-induced unfolding of the first nucleotide-binding domain from the human cystic fibrosis transmembrane conductance regulator.
View Article and Find Full Text PDFUnlabelled: Trikafta is well-known for correcting the thermal and gating defects caused by the most common cystic fibrosis mutation F508del in the human cystic fibrosis transmembrane conductance regulator even at physiological temperature. However, the exact pathway is still unclear. Here, the noncovalent interactions among two transmembrane domains (TMD 1 and TMD2), the regulatory (R) domain and two nucleotide binding domains (NBD1 and NBD2), along with the thermoring structures of NBD1, were analyzed around the active gating center.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!