Department of Pathology.
Cellular and Molecular Biology Graduate Program, and.
JCI Insight. 2020 Oct 15;5(20):136676. doi: 10.1172/jci.insight.136676.
A critical response to lysosomal membrane permeabilization (LMP) is the clearance of damaged lysosomes through a selective form of macroautophagy known as lysophagy. Although regulators of this process are emerging, whether organ- and cell-specific components contribute to the control of lysophagy remains incompletely understood. Here, we examined LMP and lysophagy in Niemann-Pick type C (NPC) disease, an autosomal recessive disorder characterized by the accumulation of unesterified cholesterol within late endosomes and lysosomes, leading to neurodegeneration and early death. We demonstrated that NPC human fibroblasts show enhanced sensitivity to lysosomal damage as a consequence of lipid storage. Moreover, we described a role for the glycan-binding F-box protein 2 (Fbxo2) in CNS lysophagy. Fbxo2 functions as a component of the S phase kinase-associated protein 1-cullin 1-F-box protein (SKP1-CUL1-SCF) ubiquitin ligase complex. Loss of Fbxo2 in mouse primary cortical cultures delayed clearance of damaged lysosomes and decreased viability after lysosomal damage. Moreover, Fbxo2 deficiency in a mouse model of NPC exacerbated deficits in motor function, enhanced neurodegeneration, and reduced survival. Collectively, our data identified a role for Fbxo2 in CNS lysophagy and establish its functional importance in NPC.
溶酶体膜通透性（LMP）的关键反应是通过一种称为溶酶体自噬的选择性形式清除受损的溶酶体。尽管该过程的调节剂正在出现，但器官和细胞特异性成分是否有助于控制溶酶体自噬仍不完全清楚。在这里，我们研究了尼曼-匹克 C 型（NPC）疾病中的 LMP 和溶酶体自噬，这是一种常染色体隐性疾病，其特征是未酯化胆固醇在内体和溶酶体中积累，导致神经退行性变和早逝。我们证明 NPC 人成纤维细胞由于脂质储存而显示出对溶酶体损伤的敏感性增强。此外，我们描述了糖结合 F 盒蛋白 2（Fbxo2）在中枢神经系统溶酶体自噬中的作用。Fbxo2 作为 S 期激酶相关蛋白 1-连接酶 1-F 盒蛋白（SKP1-CUL1-SCF）泛素连接酶复合物的一部分发挥作用。在小鼠原代皮质培养物中敲除 Fbxo2 会延迟受损溶酶体的清除，并在溶酶体损伤后降低细胞活力。此外，NPC 小鼠模型中 Fbxo2 的缺失加剧了运动功能缺陷、神经退行性变增强和存活率降低。总之，我们的数据确定了 Fbxo2 在中枢神经系统溶酶体自噬中的作用，并确立了其在 NPC 中的功能重要性。
