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

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.