a Institute of Physiology and NCCR Kidney.CH, University of Zurich , 8057 Zurich , Switzerland.
Autophagy. 2018;14(7):1157-1159. doi: 10.1080/15548627.2018.1446625. Epub 2018 May 28.
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.
胱氨酸贮积症是一种溶酶体贮积病，由于 CTNS 基因的失活突变，胱氨酸转运蛋白将胱氨酸从溶酶体中输出。溶酶体中胱氨酸的积累导致肾脏近端小管上皮细胞严重功能障碍，导致内吞作用缺陷和大量溶质丢失到尿液中。溶酶体缺陷与上皮细胞功能障碍之间的机制尚不清楚，这阻碍了疾病修饰疗法的发展。我们最近报道，胱氨酸贮积症中的溶酶体改变导致受损线粒体的自噬清除缺陷，产生氧化应激。后者会破坏紧密连接，并激活异常的 YBX3（Y 框结合蛋白 3）转录程序，导致胱氨酸贮积症细胞失去分化和顶端内吞作用缺陷。纠正主要的溶酶体缺陷、中和线粒体氧化应激、或阻断紧密连接相关的 YBX3 信号通路可挽救上皮细胞功能和内吞作用。我们的研究结果表明，这是一个级联反应，将溶酶体疾病、自噬缺陷和上皮细胞功能障碍联系起来，为胱氨酸贮积症和溶酶体贮积病提供了新的视角。
