Transcriptomic and Proteostasis Networks of CFTR and the Development of Small Molecule Modulators for the Treatment of Cystic Fibrosis Lung Disease

Strub, Matthew D.; McCray, Paul B.

doi:10.3390/genes11050546

Cited by 17 publications

(17 citation statements)

References 214 publications

(248 reference statements)

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“…In addition to these, we detect two other members of this family, DNAJA3 and DNAJA4 (Figure 4e and Figure S5a). Overall, we note a striking increase in chaperone associations with the ∆F508-CFTR bait, as compared to the WT, which is consistent with the stabilizing function of this protein family [68]. Additionally, Orkambi attenuates ∆F508 mutant associations in 18 of 24 chaperones (Supplementary Figure S5a), which is consistent with previous corrector data [67].…”

Section: Comparison Of Cftr and ∆F508-cftr Interactomes Reveal Orkamb...supporting

confidence: 89%

Proximity Profiling of the CFTR Interaction Landscape in Response to Orkambi

Iazzi

Astori

St-Germain

et al. 2022

IJMS

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Deletion of phenylalanine 508 (∆F508) of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) anion channel protein is the leading cause of Cystic Fibrosis (CF). Here, we report the analysis of CFTR and ∆F508-CFTR interactomes using BioID (proximity-dependent biotin identification), a technique that can also detect transient associations. We identified 474 high-confidence CFTR proximity-interactors, 57 of which have been previously validated, with the remainder representing novel interaction space. The ∆F508 interactome, comprising 626 proximity-interactors was markedly different from its wild type counterpart, with numerous alterations in protein associations categorized in membrane trafficking and cellular stress functions. Furthermore, analysis of the ∆F508 interactome in cells treated with Orkambi identified several interactions that were altered as a result of this drug therapy. We examined two candidate CFTR proximity interactors, VAPB and NOS1AP, in functional assays designed to assess surface delivery and overall chloride efflux. VAPB depletion impacted both CFTR surface delivery and chloride efflux, whereas NOS1AP depletion only affected the latter. The wild type and ∆F508-CFTR interactomes represent rich datasets that could be further mined to reveal additional candidates for the functional rescue of ∆F508-CFTR.

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Section: Comparison Of Cftr and ∆F508-cftr Interactomes Reveal Orkamb...supporting

confidence: 89%

Proximity Profiling of the CFTR Interaction Landscape in Response to Orkambi

Iazzi

Astori

St-Germain

et al. 2022

IJMS

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“…Moreover, proteomic studies provide a lower output of elements as compared to transcriptomic profiling. However, it must be underlined that both our study in urinary exosomes and the transcriptomic studies in airway cells indicate a significant upregulation of genes of proteasome and chaperons involved in protein degradation such as endoplasmin [34].…”

Section: No Evidence Of Strong Proteomic Modulation By Cftr Modulatorsmentioning

confidence: 80%

Urinary Exosomes of Patients with Cystic Fibrosis Unravel CFTR-Related Renal Disease

Gauthier

Pranke

Jung

et al. 2020

IJMS

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Background: The prevalence of chronic kidney disease is increased in patients with cystic fibrosis (CF). The study of urinary exosomal proteins might provide insight into the pathophysiology of CF kidney disease. Methods: Urine samples were collected from 19 CF patients (among those 7 were treated by cystic fibrosis transmembrane conductance regulator (CFTR) modulators), and 8 healthy subjects. Urine exosomal protein content was determined by high resolution mass spectrometry. Results: A heatmap of the differentially expressed proteins in urinary exosomes showed a clear separation between control and CF patients. Seventeen proteins were upregulated in CF patients (including epidermal growth factor receptor (EGFR); proteasome subunit beta type-6, transglutaminases, caspase 14) and 118 were downregulated (including glutathione S-transferases, superoxide dismutase, klotho, endosomal sorting complex required for transport, and matrisome proteins). Gene set enrichment analysis revealed 20 gene sets upregulated and 74 downregulated. Treatment with CFTR modulators yielded no significant modification of the proteomic content. These results highlight that CF kidney cells adapt to the CFTR defect by upregulating proteasome activity and that autophagy and endosomal targeting are impaired. Increased expression of EGFR and decreased expression of klotho and matrisome might play a central role in this CF kidney signature by inducing oxidation, inflammation, accelerated senescence, and abnormal tissue repair. Conclusions: Our study unravels novel insights into consequences of CFTR dysfunction in the urinary tract, some of which may have clinical and therapeutic implications.

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“…If one is to impact the health of most persons with CF, then restoration of F508del CFTR function is essential. Although F508del CFTR mutant results in a gating defect, its major biochemical consequence is a misfolded CFTR protein which rapidly undergoes ERAD [63,64].…”

Section: Lumacaftor-ivacaftormentioning

confidence: 99%

“…Other CFTR potentiators and correctors are currently in the pre-clinical or clinical phases of development, as summarized in recent reviews and listed in Table 2 [3,64,99].…”

Section: Other Modulators In the Pipelinementioning

confidence: 99%

New Therapies to Correct the Cystic Fibrosis Basic Defect

Bergeron

Cantin

2021

IJMS

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Rare diseases affect 400 million individuals worldwide and cause significant morbidity and mortality. Finding solutions for rare diseases can be very challenging for physicians and researchers. Cystic fibrosis (CF), a genetic, autosomal recessive, multisystemic, life-limiting disease does not escape this sad reality. Despite phenomenal progress in our understanding of this disease, treatment remains difficult. Until recently, therapies for CF individuals were focused on symptom management. The discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene and its product, a protein present at the apical surface of epithelial cells regulating ion transport, allowed the scientific community to learn about the basic defect in CF and to study potential therapies targeting the dysfunctional protein. In the past few years, promising therapies with the goal to restore CFTR function became available and changed the lives of several CF patients. These medications, called CFTR modulators, aim to correct, potentialize, stabilize or amplify CFTR function. Furthermore, research is ongoing to develop other targeted therapies that could be more efficient and benefit a larger proportion of the CF community. The purpose of this review is to summarize our current knowledge of CF genetics and therapies restoring CFTR function, particularly CFTR modulators and gene therapy.

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Transcriptomic and Proteostasis Networks of CFTR and the Development of Small Molecule Modulators for the Treatment of Cystic Fibrosis Lung Disease

Cited by 17 publications

References 214 publications

Proximity Profiling of the CFTR Interaction Landscape in Response to Orkambi

Proximity Profiling of the CFTR Interaction Landscape in Response to Orkambi

Urinary Exosomes of Patients with Cystic Fibrosis Unravel CFTR-Related Renal Disease

New Therapies to Correct the Cystic Fibrosis Basic Defect

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