Header

UZH-Logo

Maintenance Infos

Defective autophagy degradation and abnormal tight junction-associated signaling drive epithelial dysfunction in cystinosis


Luciani, Alessandro; Festa, Beatrice Paola; Chen, Zhiyong; Devuyst, Olivier (2018). Defective autophagy degradation and abnormal tight junction-associated signaling drive epithelial dysfunction in cystinosis. Autophagy, 14(7):1157-1159.

Abstract

Cystinosis is a lysosomal storage disease due to inactivating mutations in CTNS, the cystinosin transporter that exports cystine out of lysosomes. The lysosomal accumulation of cystine leads to severe dysfunction of the epithelial cells lining the proximal tubule of the kidney, causing defective endocytosis and massive losses of solutes in the urine. The mechanisms linking lysosomal defect and epithelial dysfunction were unknown, preventing the development of disease-modifying therapies. We recently reported that lysosomal alterations in cystinosis lead to defective autophagic clearance of damaged mitochondria, generating oxidative stress. The latter destabilizes tight junctions and activates an abnormal YBX3 (Y box binding protein 3) transcriptional program driving a loss of differentiation and defective apical endocytosis in cystinosis cells. Correction of the primary lysosomal defect, neutralization of mitochondrial oxidative stress, or blockage of tight junction-associated YBX3 signaling rescue epithelial function and endocytic uptake. Our findings suggest a cascade that links lysosomal disease, defective autophagy and epithelial dysfunction, providing new perspectives for cystinosis and lysosomal storage disorders.

Abstract

Cystinosis is a lysosomal storage disease due to inactivating mutations in CTNS, the cystinosin transporter that exports cystine out of lysosomes. The lysosomal accumulation of cystine leads to severe dysfunction of the epithelial cells lining the proximal tubule of the kidney, causing defective endocytosis and massive losses of solutes in the urine. The mechanisms linking lysosomal defect and epithelial dysfunction were unknown, preventing the development of disease-modifying therapies. We recently reported that lysosomal alterations in cystinosis lead to defective autophagic clearance of damaged mitochondria, generating oxidative stress. The latter destabilizes tight junctions and activates an abnormal YBX3 (Y box binding protein 3) transcriptional program driving a loss of differentiation and defective apical endocytosis in cystinosis cells. Correction of the primary lysosomal defect, neutralization of mitochondrial oxidative stress, or blockage of tight junction-associated YBX3 signaling rescue epithelial function and endocytic uptake. Our findings suggest a cascade that links lysosomal disease, defective autophagy and epithelial dysfunction, providing new perspectives for cystinosis and lysosomal storage disorders.

Statistics

Citations

Dimensions.ai Metrics

Altmetrics

Additional indexing

Item Type:Journal Article, refereed, further contribution
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Cell Biology, Molecular Biology
Language:English
Date:3 July 2018
Deposited On:12 Feb 2019 10:37
Last Modified:12 Feb 2019 10:42
Publisher:Taylor & Francis
ISSN:1554-8627
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1080/15548627.2018.1446625
PubMed ID:29806776

Download

Full text not available from this repository.
View at publisher

Get full-text in a library