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Cystic Fibrosis and CFTR Interactions 2.0
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Cystic Fibrosis and CFTR Interactions 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 19908

Special Issue Editors

Dr. Carlos M. Farinha

E-Mail Website
Guest Editor
BioISI – Biosystems and Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, 1749-016 Lisboa, Portugal
Interests: CFTR trafficking; CFTR interactions; rare mutations; systems biology; post-translational modifications
Special Issues, Collections and Topics in MDPI journals
Dr. Martina Gentzsch

E-Mail Website
Guest Editor
Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
Interests: epithelial ion channels; CFTR; ENaC; cystic fibrosis; theratyping; modulators; protein processing; airway disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recently, research into Cystic Fibrosis (CF) community has witnessed amazing developments with the approval of modulators to rescue the underlying defect in the most common CFTR mutations.

While modulators can now be used to treat CF in about 90% of individuals suffering from the disease, the rescue levels do not bring mutant CFTR to wild-type levels. The absence of better treatments may be due to the fact that the mechanisms of action for these drugs are still poorly understood. On the other hand, a significant proportion of individuals do not yet have a therapeutic option available that is based on the cellular and molecular defects associated with their genotypes, which prompts a continuous interest in studying disease mechanisms.

Thus, as we have seen in the past, addressing the root of the problem is still essential. CFTR interactions are a puzzle that never ceased to amaze the researchers and with the modulators now in the equation, the problem is still unsolved. Which interactions are critical to rescue CFTR? Which ones are in fact being altered by modulators? Which interactions are shared between common mutants and rare ones?

Topics of interest include:

  • Mechanisms through which interactions affect CFTR biogenesis and trafficking;
  • Response to modulators or novel RNA or DNA targeting therapeutics;
  • Change in cellular responses by approved or preclinical drugs that restore CFTR function;
  • Overcoming disease symptoms by restoring mutant CFTR functional levels;
  • Personalized therapies for rare CFTR mutations;
  • Novel insights in the regulation of CFTR expression;
  • Targeting other channels that affect dysregulations caused by the absence of functional CFTR.

Dr. Carlos M. Farinha
Dr. Martina Gentzsch
Guest Editors

Manuscript Submission Information

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Keywords

  • CFTR trafficking
  • CFTR interactions
  • rare mutations
  • CFTR modulators
  • proteostasis
  • CFTR processing
  • alternative channels
  • gene editing
  • RNA therapeutics

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Related Special Issue

Published Papers (8 papers)

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Research

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17 pages, 2394 KiB  
Article
SUMOylation Inhibition Enhances Protein Transcription under CMV Promoter: A Lesson from a Study with the F508del-CFTR Mutant
by Christian Borgo, Claudio D’Amore, Valeria Capurro, Valeria Tomati, Nicoletta Pedemonte, Valentina Bosello Travain and Mauro Salvi
Int. J. Mol. Sci. 2024, 25(4), 2302; https://doi.org/10.3390/ijms25042302 - 15 Feb 2024
Viewed by 1189
Abstract
Cystic fibrosis (CF) is a genetic disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), a selective anion channel expressed in the epithelium of various organs. The most frequent mutation is F508del. This mutation leads [...] Read more.
Cystic fibrosis (CF) is a genetic disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), a selective anion channel expressed in the epithelium of various organs. The most frequent mutation is F508del. This mutation leads to a misfolded CFTR protein quickly degraded via ubiquitination in the endoplasmic reticulum. Although preventing ubiquitination stabilizes the protein, functionality is not restored due to impaired plasma membrane transport. However, inhibiting the ubiquitination process can improve the effectiveness of correctors which act as chemical chaperones, facilitating F508del CFTR trafficking to the plasma membrane. Previous studies indicate a crosstalk between SUMOylation and ubiquitination in the regulation of CFTR. In this study, we investigated the potential of inhibiting SUMOylation to increase the effects of correctors and enhance the rescue of the F508del mutant across various cell models. In the widely used CFBE41o-cell line expressing F508del-CFTR, inhibiting SUMOylation substantially boosted F508del expression, thereby increasing the efficacy of correctors. Interestingly, this outcome did not result from enhanced stability of the mutant channel, but rather from augmented cytomegalovirus (CMV) promoter-mediated gene expression of F508del-CFTR. Notably, CFTR regulated by endogenous promoters in multiple cell lines or patient cells was not influenced by SUMOylation inhibitors. Full article
(This article belongs to the Special Issue Cystic Fibrosis and CFTR Interactions 2.0)
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15 pages, 1604 KiB  
Article
Personalized CFTR Modulator Therapy for G85E and N1303K Homozygous Patients with Cystic Fibrosis
by Simon Y. Graeber, Anita Balázs, Niklas Ziegahn, Tihomir Rubil, Constanze Vitzthum, Linus Piehler, Marika Drescher, Kathrin Seidel, Alexander Rohrbach, Jobst Röhmel, Stephanie Thee, Julia Duerr, Marcus A. Mall and Mirjam Stahl
Int. J. Mol. Sci. 2023, 24(15), 12365; https://doi.org/10.3390/ijms241512365 - 2 Aug 2023
Cited by 14 | Viewed by 2243
Abstract
CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) has been approved for people with CF and at least one F508del allele in Europe. In the US, the ETI label has been expanded to 177 rare CFTR mutations responsive in Fischer rat thyroid cells, including G85E [...] Read more.
CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) has been approved for people with CF and at least one F508del allele in Europe. In the US, the ETI label has been expanded to 177 rare CFTR mutations responsive in Fischer rat thyroid cells, including G85E, but not N1303K. However, knowledge on the effect of ETI on G85E or N1303K CFTR function remains limited. In vitro effects of ETI were measured in primary human nasal epithelial cultures (pHNECs) of a G85E homozygous patient and an N1303K homozygous patient. Effects of ETI therapy in vivo in these patients were assessed using clinical outcomes, including multiple breath washout and lung MRI, and the CFTR biomarkers sweat chloride concentration (SCC), nasal potential difference (NPD) and intestinal current measurement (ICM), before and after initiation of ETI. ETI increased CFTR-mediated chloride transport in G85E/G85E and N1303K/N1303K pHNECs. In the G85E/G85E and the N1303K/N1303K patient, we observed an improvement in lung function, SCC, and CFTR function in the respiratory and rectal epithelium after initiation of ETI. The approach of combining preclinical in vitro testing with subsequent in vivo verification can facilitate access to CFTR modulator therapy and enhance precision medicine for patients carrying rare CFTR mutations. Full article
(This article belongs to the Special Issue Cystic Fibrosis and CFTR Interactions 2.0)
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Review

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11 pages, 726 KiB  
Review
Beyond Borders of the Cell: How Extracellular Vesicles Shape COVID-19 for People with Cystic Fibrosis
by Ewelina D. Hejenkowska, Hayrettin Yavuz and Agnieszka Swiatecka-Urban
Int. J. Mol. Sci. 2024, 25(7), 3713; https://doi.org/10.3390/ijms25073713 - 27 Mar 2024
Cited by 1 | Viewed by 1509
Abstract
The interaction between extracellular vesicles (EVs) and SARS-CoV-2, the virus causing COVID-19, especially in people with cystic fibrosis (PwCF) is insufficiently studied. EVs are small membrane-bound particles involved in cell–cell communications in different physiological and pathological conditions, including inflammation and infection. The CF [...] Read more.
The interaction between extracellular vesicles (EVs) and SARS-CoV-2, the virus causing COVID-19, especially in people with cystic fibrosis (PwCF) is insufficiently studied. EVs are small membrane-bound particles involved in cell–cell communications in different physiological and pathological conditions, including inflammation and infection. The CF airway cells release EVs that differ from those released by healthy cells and may play an intriguing role in regulating the inflammatory response to SARS-CoV-2. On the one hand, EVs may activate neutrophils and exacerbate inflammation. On the other hand, EVs may block IL-6, a pro-inflammatory cytokine associated with severe COVID-19, and protect PwCF from adverse outcomes. EVs are regulated by TGF-β signaling, essential in different disease states, including COVID-19. Here, we review the knowledge, identify the gaps in understanding, and suggest future research directions to elucidate the role of EVs in PwCF during COVID-19. Full article
(This article belongs to the Special Issue Cystic Fibrosis and CFTR Interactions 2.0)
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34 pages, 3711 KiB  
Review
Functional Consequences of CFTR Interactions in Cystic Fibrosis
by Yashaswini Ramananda, Anjaparavanda P. Naren and Kavisha Arora
Int. J. Mol. Sci. 2024, 25(6), 3384; https://doi.org/10.3390/ijms25063384 - 16 Mar 2024
Cited by 6 | Viewed by 5297
Abstract
Cystic fibrosis (CF) is a fatal autosomal recessive disorder caused by the loss of function mutations within a single gene for the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). CFTR is a chloride channel that regulates ion and fluid transport across various epithelia. The [...] Read more.
Cystic fibrosis (CF) is a fatal autosomal recessive disorder caused by the loss of function mutations within a single gene for the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). CFTR is a chloride channel that regulates ion and fluid transport across various epithelia. The discovery of CFTR as the CF gene and its cloning in 1989, coupled with extensive research that went into the understanding of the underlying biological mechanisms of CF, have led to the development of revolutionary therapies in CF that we see today. The highly effective modulator therapies have increased the survival rates of CF patients and shifted the epidemiological landscape and disease prognosis. However, the differential effect of modulators among CF patients and the presence of non-responders and ineligible patients underscore the need to develop specialized and customized therapies for a significant number of patients. Recent advances in the understanding of the CFTR structure, its expression, and defined cellular compositions will aid in developing more precise therapies. As the lifespan of CF patients continues to increase, it is becoming critical to clinically address the extra-pulmonary manifestations of CF disease to improve the quality of life of the patients. In-depth analysis of the molecular signature of different CF organs at the transcriptional and post-transcriptional levels is rapidly advancing and will help address the etiological causes and variability of CF among patients and develop precision medicine in CF. In this review, we will provide an overview of CF disease, leading to the discovery and characterization of CFTR and the development of CFTR modulators. The later sections of the review will delve into the key findings derived from single-molecule and single-cell-level analyses of CFTR, followed by an exploration of disease-relevant protein complexes of CFTR that may ultimately define the etiological course of CF disease. Full article
(This article belongs to the Special Issue Cystic Fibrosis and CFTR Interactions 2.0)
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19 pages, 2067 KiB  
Review
Pathogenic Relationships in Cystic Fibrosis and Renal Diseases: CFTR, SLC26A9 and Anoctamins
by Karl Kunzelmann, Jiraporn Ousingsawat, Andre Kraus, Julien H. Park, Thorsten Marquardt, Rainer Schreiber and Björn Buchholz
Int. J. Mol. Sci. 2023, 24(17), 13278; https://doi.org/10.3390/ijms241713278 - 26 Aug 2023
Cited by 4 | Viewed by 2510
Abstract
The Cl−-transporting proteins CFTR, SLC26A9, and anoctamin (ANO1; ANO6) appear to have more in common than initially suspected, as they all participate in the pathogenic process and clinical outcomes of airway and renal diseases. In the present review, we will therefore [...] Read more.
The Cl−-transporting proteins CFTR, SLC26A9, and anoctamin (ANO1; ANO6) appear to have more in common than initially suspected, as they all participate in the pathogenic process and clinical outcomes of airway and renal diseases. In the present review, we will therefore concentrate on recent findings concerning electrolyte transport in the airways and kidneys, and the role of CFTR, SLC26A9, and the anoctamins ANO1 and ANO6. Special emphasis will be placed on cystic fibrosis and asthma, as well as renal alkalosis and polycystic kidney disease. In essence, we will summarize recent evidence indicating that CFTR is the only relevant secretory Cl− channel in airways under basal (nonstimulated) conditions and after stimulation by secretagogues. Information is provided on the expressions of ANO1 and ANO6, which are important for the correct expression and function of CFTR. In addition, there is evidence that the Cl− transporter SLC26A9 expressed in the airways may have a reabsorptive rather than a Cl−-secretory function. In the renal collecting ducts, bicarbonate secretion occurs through a synergistic action of CFTR and the Cl−/HCO3− transporter SLC26A4 (pendrin), which is probably supported by ANO1. Finally, in autosomal dominant polycystic kidney disease (ADPKD), the secretory function of CFTR in renal cyst formation may have been overestimated, whereas ANO1 and ANO6 have now been shown to be crucial in ADPKD and therefore represent new pharmacological targets for the treatment of polycystic kidney disease. Full article
(This article belongs to the Special Issue Cystic Fibrosis and CFTR Interactions 2.0)
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20 pages, 3309 KiB  
Review
A Proteomic Survey of the Cystic Fibrosis Transmembrane Conductance Regulator Surfaceome
by Melissa Iazzi, Sara Sadeghi and Gagan D. Gupta
Int. J. Mol. Sci. 2023, 24(14), 11457; https://doi.org/10.3390/ijms241411457 - 14 Jul 2023
Cited by 2 | Viewed by 2028
Abstract
The aim of this review article is to collate recent contributions of proteomic studies to cystic fibrosis transmembrane conductance regulator (CFTR) biology. We summarize advances from these studies and create an accessible resource for future CFTR proteomic efforts. We focus our attention on [...] Read more.
The aim of this review article is to collate recent contributions of proteomic studies to cystic fibrosis transmembrane conductance regulator (CFTR) biology. We summarize advances from these studies and create an accessible resource for future CFTR proteomic efforts. We focus our attention on the CFTR interaction network at the cell surface, thus generating a CFTR ‘surfaceome’. We review the main findings about CFTR interactions and highlight several functional categories amongst these that could lead to the discovery of potential biomarkers and drug targets for CF. Full article
(This article belongs to the Special Issue Cystic Fibrosis and CFTR Interactions 2.0)
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15 pages, 3168 KiB  
Review
Tissue-Specific Regulation of CFTR Gene Expression
by Clara Blotas, Claude Férec and Stéphanie Moisan
Int. J. Mol. Sci. 2023, 24(13), 10678; https://doi.org/10.3390/ijms241310678 - 26 Jun 2023
Cited by 6 | Viewed by 2266
Abstract
More than 2000 variations are described within the CFTR (Cystic Fibrosis Transmembrane Regulator) gene and related to large clinical issues from cystic fibrosis to mono-organ diseases. Although these CFTR-associated diseases have been well documented, a large phenotype spectrum is observed [...] Read more.
More than 2000 variations are described within the CFTR (Cystic Fibrosis Transmembrane Regulator) gene and related to large clinical issues from cystic fibrosis to mono-organ diseases. Although these CFTR-associated diseases have been well documented, a large phenotype spectrum is observed and correlations between phenotypes and genotypes are still not well established. To address this issue, we present several regulatory elements that can modulate CFTR gene expression in a tissue-specific manner. Among them, cis-regulatory elements act through chromatin loopings and take part in three-dimensional structured organization. With tissue-specific transcription factors, they form chromatin modules and can regulate gene expression. Alterations of specific regulations can impact and modulate disease expressions. Understanding all those mechanisms highlights the need to expand research outside the gene to enhance our knowledge. Full article
(This article belongs to the Special Issue Cystic Fibrosis and CFTR Interactions 2.0)
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15 pages, 1067 KiB  
Review
It Takes Two to Tango! Protein–Protein Interactions behind cAMP-Mediated CFTR Regulation
by Alessandra Murabito, Janki Bhatt and Alessandra Ghigo
Int. J. Mol. Sci. 2023, 24(13), 10538; https://doi.org/10.3390/ijms241310538 - 23 Jun 2023
Cited by 4 | Viewed by 2128
Abstract
Over the last fifteen years, with the approval of the first molecular treatments, a breakthrough era has begun for patients with cystic fibrosis (CF), the rare genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). These [...] Read more.
Over the last fifteen years, with the approval of the first molecular treatments, a breakthrough era has begun for patients with cystic fibrosis (CF), the rare genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). These molecules, known as CFTR modulators, have led to unprecedented improvements in the lung function and quality of life of most CF patients. However, the efficacy of these drugs is still suboptimal, and the clinical response is highly variable even among individuals bearing the same mutation. Furthermore, not all patients carrying rare CFTR mutations are eligible for CFTR modulator therapies, indicating the need for alternative and/or add-on therapeutic approaches. Because the second messenger 3′,5′-cyclic adenosine monophosphate (cAMP) represents the primary trigger for CFTR activation and a major regulator of different steps of the life cycle of the channel, there is growing interest in devising ways to fine-tune the cAMP signaling pathway for therapeutic purposes. This review article summarizes current knowledge regarding the role of cAMP signalosomes, i.e., multiprotein complexes bringing together key enzymes of the cAMP pathway, in the regulation of CFTR function, and discusses how modulating this signaling cascade could be leveraged for therapeutic intervention in CF. Full article
(This article belongs to the Special Issue Cystic Fibrosis and CFTR Interactions 2.0)
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