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Multiomics analysis of a DNAH5-mutated PCD organoid model revealed the key role of the TGF-β/BMP and Notch pathways in epithelial differentiation and the immune response in DNAH5-mutated patients

ABSTRACT: Dynein axonemal heavy chain 5 (DNAH5) is the most mutated gene in primary ciliary dyskinesia (PCD), leading to abnormal cilia ultrastructure and function. Few studies have revealed the genetic characteristics and pathogenetic mechanisms of PCD caused by DNAH5 mutation. Here, we established a child PCD airway organoid directly from the bronchoscopic biopsy of a patient with DNAH5 mutation. We found abnormal ciliary function and a decreased immune response caused by DNAH5 mutation through single-cell RNA sequencing (scRNA-seq).

ORGANISM(S): Homo sapiens

PROVIDER: GSE217596 | GEO | 2022/11/12

REPOSITORIES: GEO

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Multiomics analysis of a DNAH5-mutated PCD organoid model revealed the key role of the TGF-β/BMP and Notch pathways in epithelial differentiation and the immune response in DNAH5-mutated patients

Project description:Dynein axonemal heavy chain 5 (DNAH5) is the most mutated gene in primary ciliary dyskinesia (PCD), leading to abnormal cilia ultrastructure and function. Few studies have revealed the genetic characteristics and pathogenetic mechanisms of PCD caused by DNAH5 mutation. Here, we established a child PCD airway organoid directly from the bronchoscopic biopsy of a patient with DNAH5 mutation. We found abnormal ciliary function and a decreased immune response caused by DNAH5 mutation through proteomic analyses.

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2024-02-12 | PXD045935 | Pride

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Project description:Molecular chaperones are abundant cellular proteins that promote the folding, function and macromolecular assembly of a diverse set of substrate proteins, also known as clients. Regulation of chaperone specificity and function involves association with a growing set of distinct cofactors, or cochaperones. How these client, co-chaperone and chaperone interactions in vivo underpin the proteostasis network during development and disease remains unclear. We have combined mouse genetics, imaging and quantitative proteomics to systematically characterize a chaperone-cochaperone-client interaction network in mammalian motile ciliated cells. We uncover ZMYND10 to act as a specificity factor for the immunophilin cochaperone FKBP8 and HSP90 chaperone for the biosynthesis of the heavy chains of axonemal dyneins required for cilial beat. We establish a series of protein-protein interactions during cytoplasmic pre-assembly of macromolecular dynein motors, some of which are directly ZMYND10-dependent. In the absence of ZMYND10, failure of these interactions results in misfolded and unstable dynein heavy chains, which together with non-functional folding intermediates, are targeted for degradation. We propose that the motile ciliopathy Primary Ciliary Dyskinesia (PCD), such as seen in Zmynd10 mutants, be reconsidered as a disorder of protein folding, which opens new avenues for development of therapeutics.

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Genome-wide gene expression analysis in primary ciliary dyskinesia patients

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Multiomics analysis of a DNAH5-mutated PCD organoid model revealed the key role of the TGF-β/BMP and Notch pathways in epithelial differentiation and the immune response in DNAH5-mutated patients

Project description:Multiomics analysis of a DNAH5-mutated PCD organoid model revealed the key role of the TGF-β/BMP and Notch pathways in epithelial differentiation and the immune response in DNAH5-mutated patients

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