The Usher syndrome 1C protein harmonin regulates canonical Wnt signaling
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Jessica Schaefer
- Nicole Wenck
- Katharina Janik
- Joshua Linnert
- Katarina Stingl
- Susanne Kohl
- Kerstin Nagel-Wolfrum
- Uwe Wolfrum
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000936427600001&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.3389/fcell.2023.1130058
- Externe Identifier
- Clarivate Analytics Document Solution ID: 9D9PH
- PubMed Identifier: 36846582
- ISSN
- 2296-634X
- Zeitschrift
- FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
- Schlüsselwörter
- Usher syndrome
- USH1C
- beta-catenin
- translational read-through inducing drugs
- ataluren
- PTC124
- colorectal cancer
- translational read-through
- wnt signaling pathway
- Artikelnummer
- ARTN 1130058
- Datum der Veröffentlichung
- 2023
- Status
- Published
- Titel
- The Usher syndrome 1C protein harmonin regulates canonical Wnt signaling
- Sub types
- Article
- Ausgabe der Zeitschrift
- 11
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Abstract
- <jats:p>Human Usher syndrome (USH) is the most common form of hereditary combined deaf-blindness. USH is a complex genetic disorder, and the pathomechanisms underlying the disease are far from being understood, especially in the eye and retina. The <jats:italic>USH1C</jats:italic> gene encodes the scaffold protein harmonin which organizes protein networks due to binary interactions with other proteins, such as all USH proteins. Interestingly, only the retina and inner ear show a disease-related phenotype, although <jats:italic>USH1C</jats:italic>/harmonin is almost ubiquitously expressed in the human body and upregulated in colorectal cancer. We show that harmonin binds to <jats:italic>β</jats:italic>-catenin, the key effector of the canonical Wnt (cWnt) signaling pathway. We also demonstrate the interaction of the scaffold protein <jats:italic>USH1C</jats:italic>/harmonin with the stabilized acetylated <jats:italic>β</jats:italic>-catenin, especially in nuclei. In HEK293T cells, overexpression of <jats:italic>USH1C</jats:italic>/harmonin significantly reduced cWnt signaling, but a <jats:italic>USH1C</jats:italic>-R31* mutated form did not. Concordantly, we observed an increase in cWnt signaling in dermal fibroblasts derived from an <jats:italic>USH1C</jats:italic><jats:sup>R31*/R80Pfs*69</jats:sup> patient compared with healthy donor cells. RNAseq analysis reveals that both the expression of genes related to the cWnt signaling pathway and cWnt target genes were significantly altered in USH1C patient-derived fibroblasts compared to healthy donor cells. Finally, we show that the altered cWnt signaling was reverted in USH1C patient fibroblast cells by the application of Ataluren, a small molecule suitable to induce translational read-through of nonsense mutations, hereby restoring some USH1C expression. Our results demonstrate a cWnt signaling phenotype in USH establishing <jats:italic>USH1C</jats:italic>/harmonin as a suppressor of the cWnt/<jats:italic>β</jats:italic>-catenin pathway.</jats:p>
- Autoren
- Jessica Schäfer
- Nicole Wenck
- Katharina Janik
- Joshua Linnert
- Katarina Stingl
- Susanne Kohl
- Kerstin Nagel-Wolfrum
- Uwe Wolfrum
- DOI
- 10.3389/fcell.2023.1130058
- eISSN
- 2296-634X
- Zeitschrift
- Frontiers in Cell and Developmental Biology
- Online publication date
- 2023
- Status
- Published online
- Herausgeber
- Frontiers Media SA
- Herausgeber URL
- http://dx.doi.org/10.3389/fcell.2023.1130058
- Datum der Datenerfassung
- 2023
- Titel
- The Usher syndrome 1C protein harmonin regulates canonical Wnt signaling
- Ausgabe der Zeitschrift
- 11
Data source: Crossref
- Abstract
- Human Usher syndrome (USH) is the most common form of hereditary combined deaf-blindness. USH is a complex genetic disorder, and the pathomechanisms underlying the disease are far from being understood, especially in the eye and retina. The <i>USH1C</i> gene encodes the scaffold protein harmonin which organizes protein networks due to binary interactions with other proteins, such as all USH proteins. Interestingly, only the retina and inner ear show a disease-related phenotype, although <i>USH1C</i>/harmonin is almost ubiquitously expressed in the human body and upregulated in colorectal cancer. We show that harmonin binds to <i>β</i>-catenin, the key effector of the canonical Wnt (cWnt) signaling pathway. We also demonstrate the interaction of the scaffold protein <i>USH1C</i>/harmonin with the stabilized acetylated <i>β</i>-catenin, especially in nuclei. In HEK293T cells, overexpression of <i>USH1C</i>/harmonin significantly reduced cWnt signaling, but a <i>USH1C</i>-R31* mutated form did not. Concordantly, we observed an increase in cWnt signaling in dermal fibroblasts derived from an <i>USH1C</i> <sup>R31*/R80Pfs*69</sup> patient compared with healthy donor cells. RNAseq analysis reveals that both the expression of genes related to the cWnt signaling pathway and cWnt target genes were significantly altered in USH1C patient-derived fibroblasts compared to healthy donor cells. Finally, we show that the altered cWnt signaling was reverted in USH1C patient fibroblast cells by the application of Ataluren, a small molecule suitable to induce translational read-through of nonsense mutations, hereby restoring some USH1C expression. Our results demonstrate a cWnt signaling phenotype in USH establishing <i>USH1C</i>/harmonin as a suppressor of the cWnt/<i>β</i>-catenin pathway.
- Addresses
- Institute of Molecular Physiology, Molecular Cell Biology and Photoreceptor Cell Biology, Johannes Gutenberg University Mainz, Mainz, Germany.
- Autoren
- Jessica Schäfer
- Nicole Wenck
- Katharina Janik
- Joshua Linnert
- Katarina Stingl
- Susanne Kohl
- Kerstin Nagel-Wolfrum
- Uwe Wolfrum
- DOI
- 10.3389/fcell.2023.1130058
- eISSN
- 2296-634X
- Externe Identifier
- PubMed Identifier: 36846582
- PubMed Central ID: PMC9944737
- Funding acknowledgements
- Deutsche Forschungsgemeinschaft: 399443882 399487434 398539671
- Foundation Fighting Blindness: PPA-0717-0719-RAD TA-GT-0316-0694-JGU
- Open access
- true
- ISSN
- 2296-634X
- Zeitschrift
- Frontiers in cell and developmental biology
- Sprache
- eng
- Medium
- Electronic-eCollection
- Online publication date
- 2023
- Open access status
- Open Access
- Paginierung
- 1130058
- Datum der Veröffentlichung
- 2023
- Status
- Published
- Publisher licence
- CC BY
- Datum der Datenerfassung
- 2023
- Titel
- The Usher syndrome 1C protein harmonin regulates canonical Wnt signaling.
- Sub types
- research-article
- Journal Article
- Ausgabe der Zeitschrift
- 11
Files
https://www.frontiersin.org/articles/10.3389/fcell.2023.1130058/pdf https://europepmc.org/articles/PMC9944737?pdf=render
Data source: Europe PubMed Central
- Abstract
- Human Usher syndrome (USH) is the most common form of hereditary combined deaf-blindness. USH is a complex genetic disorder, and the pathomechanisms underlying the disease are far from being understood, especially in the eye and retina. The USH1C gene encodes the scaffold protein harmonin which organizes protein networks due to binary interactions with other proteins, such as all USH proteins. Interestingly, only the retina and inner ear show a disease-related phenotype, although USH1C/harmonin is almost ubiquitously expressed in the human body and upregulated in colorectal cancer. We show that harmonin binds to β-catenin, the key effector of the canonical Wnt (cWnt) signaling pathway. We also demonstrate the interaction of the scaffold protein USH1C/harmonin with the stabilized acetylated β-catenin, especially in nuclei. In HEK293T cells, overexpression of USH1C/harmonin significantly reduced cWnt signaling, but a USH1C-R31* mutated form did not. Concordantly, we observed an increase in cWnt signaling in dermal fibroblasts derived from an USH1C R31*/R80Pfs*69 patient compared with healthy donor cells. RNAseq analysis reveals that both the expression of genes related to the cWnt signaling pathway and cWnt target genes were significantly altered in USH1C patient-derived fibroblasts compared to healthy donor cells. Finally, we show that the altered cWnt signaling was reverted in USH1C patient fibroblast cells by the application of Ataluren, a small molecule suitable to induce translational read-through of nonsense mutations, hereby restoring some USH1C expression. Our results demonstrate a cWnt signaling phenotype in USH establishing USH1C/harmonin as a suppressor of the cWnt/β-catenin pathway.
- Date of acceptance
- 2023
- Autoren
- Jessica Schäfer
- Nicole Wenck
- Katharina Janik
- Joshua Linnert
- Katarina Stingl
- Susanne Kohl
- Kerstin Nagel-Wolfrum
- Uwe Wolfrum
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/36846582
- DOI
- 10.3389/fcell.2023.1130058
- Externe Identifier
- PubMed Central ID: PMC9944737
- ISSN
- 2296-634X
- Zeitschrift
- Front Cell Dev Biol
- Schlüsselwörter
- USH1C
- Usher syndrome
- ataluren/PTC124
- colorectal cancer
- translational read-through
- translational read-through inducing drugs
- wnt signaling pathway
- β-catenin
- Sprache
- eng
- Country
- Switzerland
- Paginierung
- 1130058
- PII
- 1130058
- Datum der Veröffentlichung
- 2023
- Status
- Published online
- Titel
- The Usher syndrome 1C protein harmonin regulates canonical Wnt signaling.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 11
Data source: PubMed
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