CLN7是调节溶酶体功能的细胞器氯离子通道

神经元蜡样脂褐质沉积症（NCL）是一种常染色体隐性溶酶体贮积症。晚发型NCL（vLINCL）的一种变异形式是由溶酶体膜蛋白CLN7的突变引起的，其功能一直不明。在这里，我们发现CLN7是一种新型溶酶体内氯离子通道。过表达CLN7可增加溶酶体内氯离子电流，并通过Ca2+/钙调蛋白依赖性方式增大溶酶体。人源CLN7及其酵母同源物表现出氯离子通道的特征，并对氯离子通道阻断剂敏感。此外，CLN7还能调节溶酶体氯离子传导、溶酶体腔内pH值和膜电位，并通过瞬时受体电位粘脂蛋白1（TRPML1）促进溶酶体Ca2+的释放。小鼠敲除CLN7会出现与vLINCL患者相似的病理特征，包括视网膜变性和自发荧光脂褐素。CLN7的致病突变导致氯离子通透性降低，这表明重建溶酶体Cl-稳态可能是治疗vLINCL的有效策略。Neuronal ceroid lipofuscinosis (NCL) is an autosomal recessive lysosomal storage disorder. One variant form of late-onset NCL (vLINCL) is caused by mutations in the lysosomal membrane protein CLN7, whose function has long remained elusive. Here, we identify CLN7 as a novel intralysosomal chloride channel. Overexpression of CLN7 increases intralysosomal chloride currents and enlarges lysosomes in a Ca²⁺/calmodulin-dependent manner. Human CLN7 and its yeast orthologs exhibit the hallmarks of chloride channels and are sensitive to chloride channel blockers. Furthermore, CLN7 regulates lysosomal chloride conductance, intralysosomal pH and membrane potential, and promotes lysosomal Ca²⁺ release via transient receptor potential mucolipin 1 (TRPML1). Mice with Cln7 knockout exhibit pathological features similar to those of vLINCL patients, including retinal degeneration and autofluorescent lipofuscin. Pathogenic mutations in CLN7 reduce chloride permeability, suggesting that restoring lysosomal Cl⁻ homeostasis may represent an effective therapeutic strategy for vLINCL.