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

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.

KEYWORDS:

• autophagy
• cell differentiation
• kidney tubule
• lysosome storage disease
• mitochondrial oxidative stress
• receptor-mediated endocytosis

Disclosure of potential conflict of interest

The authors declare no competing financial interests.

Additional information

Funding

We are grateful to Fonds National de la Recherche Scientifique and the Fonds de la Recherche Scientifique Médicale (Brussels, Belgium), the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 305608 (EURenOmics) and under the grant agreement n°608847 (IKPP2), the Cystinosis Research Foundation (Irvine, CA, USA) (project grant CRFS-2017-007), the Swiss National Science Foundation (project grant 31003A-169850), the clinical research priority programs (KFSP) Molecular Imaging Network Zurich (MINZ) and RADIZ (Rare Disease Initiative Zurich) of the UZH, the Dutch Kidney Foundation (project grant 16OI06) and the Swiss National Centre of Competence in Research (NCCR) Kidney Control of Homeostasis (Kidney.CH) for support and Junior Grant (to A.L.).