Institute of Physiology and NCCR Kidney.CH, University of Zurich, 8057, Zurich, Switzerland.
Department of Nephrology and Hypertension, Hubrecht Institute and University Medical Center Utrecht, 3584, Utrecht, The Netherlands.
Nat Commun. 2018 Jan 11;9(1):161. doi: 10.1038/s41467-017-02536-7.
The endolysosomal system sustains the reabsorptive activity of specialized epithelial cells. Lysosomal storage diseases such as nephropathic cystinosis cause a major dysfunction of epithelial cells lining the kidney tubule, resulting in massive losses of vital solutes in the urine. The mechanisms linking lysosomal defects and epithelial dysfunction remain unknown, preventing the development of disease-modifying therapies. Here we demonstrate, by combining genetic and pharmacologic approaches, that lysosomal dysfunction in cystinosis results in defective autophagy-mediated clearance of damaged mitochondria. This promotes the generation of oxidative stress that stimulates Gα12/Src-mediated phosphorylation of tight junction ZO-1 and triggers a signaling cascade involving ZO-1-associated Y-box factor ZONAB, which leads to cell proliferation and transport defects. Correction of the primary lysosomal defect, neutralization of mitochondrial oxidative stress, and blockage of tight junction-associated ZONAB signaling rescue the epithelial function. We suggest a link between defective lysosome-autophagy degradation pathways and epithelial dysfunction, providing new therapeutic perspectives for lysosomal storage disorders.
内溶酶体系统维持着特化上皮细胞的重吸收活性。溶酶体贮积症（如肾性胱氨酸病）导致肾小管衬里上皮细胞的主要功能障碍，导致大量生命必需溶质在尿液中丢失。将溶酶体缺陷与上皮功能障碍联系起来的机制尚不清楚，从而阻止了疾病修饰疗法的发展。在这里，我们通过结合遗传和药理学方法证明，胱氨酸病中的溶酶体功能障碍导致受损线粒体的自噬清除缺陷。这会促进氧化应激的产生，刺激 Gα12/Src 介导的紧密连接 ZO-1 的磷酸化，并引发涉及 ZO-1 相关 Y 框因子 ZONAB 的信号级联反应，从而导致细胞增殖和转运缺陷。纠正原发性溶酶体缺陷、中和线粒体氧化应激以及阻断紧密连接相关的 ZONAB 信号转导可挽救上皮功能。我们提出了溶酶体-自噬降解途径缺陷与上皮功能障碍之间的联系，为溶酶体贮积症提供了新的治疗前景。
