Lysosomes are central organelles for cellular degradation and energy metabolism. Neuronal ceroid lipofuscinoses (NCLs) are a group of the most common neurodegenerative lysosomal storage disorders characterized by intracellular accumulation of ceroid in neurons. Mutations in KCTD7 , a gene encoding an adaptor of the CUL3-RING E3 ubiquitin ligase (CRL3) complex, are categorized as a unique NCL subtype. However, the underlying mechanisms remain elusive. Here, we report various lysosomal and autophagic defects in KCTD7-deficient cells. Mechanistically, the CRL3-KCTD7 complex degrades CLN5, whereas patient-derived KCTD7 mutations disrupt the interaction between KCTD7-CUL3 or KCTD7-CLN5 and ultimately lead to excessive accumulation of CLN5. The accumulated CLN5 disrupts the interaction between CLN6/8 and lysosomal enzymes at the endoplasmic reticulum (ER), subsequently impairing ER-to-Golgi trafficking of lysosomal enzymes. Our findings reveal previously unrecognized roles of KCTD7-mediated CLN5 proteolysis in lysosomal homeostasis and demonstrate that KCTD7 and CLN5 are biochemically linked and function in a common neurodegenerative pathway.

中文翻译：

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KCTD7 突变通过 CLN5 积累损害溶酶体酶的运输，导致神经元蜡质脂褐质沉积症


溶酶体是细胞降解和能量代谢的中心细胞器。神经元蜡样质脂褐质沉积症（NCL）是一组最常见的神经退行性溶酶体贮积症，其特征是神经元蜡样质在细胞内积聚。突变在KCTD7是编码 CUL3-RING E3 泛素连接酶 (CRL3) 复合物接头的基因，被归类为独特的 NCL 亚型。然而，潜在的机制仍然难以捉摸。在这里，我们报告了 KCTD7 缺陷细胞中的各种溶酶体和自噬缺陷。从机制上讲，CRL3-KCTD7 复合物会降解 CLN5，而患者来源的 KCTD7 突变会破坏 KCTD7-CUL3 或 KCTD7-CLN5 之间的相互作用，最终导致 CLN5 过度积累。积累的 CLN5 破坏了 CLN6/8 和内质网 (ER) 溶酶体酶之间的相互作用，随后损害了溶酶体酶从 ER 到高尔基体的运输。我们的研究结果揭示了之前未被认识到的 KCTD7 介导的 CLN5 蛋白水解在溶酶体稳态中的作用，并证明 KCTD7 和 CLN5 在生化上相关，并在共同的神经退行性途径中发挥作用。