Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald, Germany.
J Am Soc Nephrol. 2020 Aug;31(8):1796-1814. doi: 10.1681/ASN.2019090960. Epub 2020 Jul 8.
The mechanisms balancing proteostasis in glomerular cells are unknown. Mucolipidosis (ML) II and III are rare lysosomal storage disorders associated with mutations of the Golgi-resident GlcNAc-1-phosphotransferase, which generates mannose 6-phosphate residues on lysosomal enzymes. Without this modification, lysosomal enzymes are missorted to the extracellular space, which results in lysosomal dysfunction of many cell types. Patients with MLII present with severe skeletal abnormalities, multisystemic symptoms, and early death; the clinical course in MLIII is less progressive. Despite dysfunction of a major degradative pathway, renal and glomerular involvement is rarely reported, suggesting organ-specific compensatory mechanisms.
MLII mice were generated and compared with an established MLIII model to investigate the balance of protein synthesis and degradation, which reflects glomerular integrity. Proteinuria was assessed in patients. High-resolution confocal microscopy and functional assays identified proteins to deduce compensatory modes of balancing proteostasis.
Patients with MLII but not MLIII exhibited microalbuminuria. MLII mice showed lysosomal enzyme missorting and several skeletal alterations, indicating that they are a useful model. In glomeruli, both MLII and MLIII mice exhibited reduced levels of lysosomal enzymes and enlarged lysosomes with abnormal storage material. Nevertheless, neither model had detectable morphologic or functional glomerular alterations. The models rebalance proteostasis in two ways: MLII mice downregulate protein translation and increase the integrated stress response, whereas MLIII mice upregulate the proteasome system in their glomeruli. Both MLII and MLIII downregulate the protein complex mTORC1 (mammalian target of rapamycin complex 1) signaling, which decreases protein synthesis.
Severe lysosomal dysfunction leads to microalbuminuria in some patients with mucolipidosis. Mouse models indicate distinct compensatory pathways that balance proteostasis in MLII and MLIII.
肾小球细胞中蛋白质平衡的机制尚不清楚。黏脂贮积症（ML）II 型和 III 型是罕见的溶酶体贮积症，与高尔基驻留的 GlcNAc-1-磷酸转移酶的突变有关，该酶在溶酶体酶上生成甘露糖 6-磷酸残基。没有这种修饰，溶酶体酶就会错误分拣到细胞外空间，导致许多细胞类型的溶酶体功能障碍。MLII 型患者表现出严重的骨骼异常、多系统症状和早逝；MLIII 型的临床病程进展较慢。尽管主要降解途径的功能障碍，但很少有肾脏和肾小球受累的报道，这表明存在器官特异性的代偿机制。
生成 MLII 型小鼠，并与已建立的 MLIII 型模型进行比较，以研究反映肾小球完整性的蛋白质合成和降解的平衡。评估患者的蛋白尿。高分辨率共聚焦显微镜和功能测定鉴定了蛋白质，以推断平衡蛋白质稳态的代偿模式。
MLII 型患者但不是 MLIII 型患者出现微量白蛋白尿。MLII 型小鼠表现出溶酶体酶错误分拣和几种骨骼改变，表明它们是一种有用的模型。在肾小球中，MLII 型和 MLIII 型小鼠的溶酶体酶水平降低，溶酶体增大，含有异常储存物质。然而，两种模型均未检测到形态或功能的肾小球改变。这些模型通过两种方式重新平衡蛋白质稳态：MLII 型小鼠下调蛋白质翻译并增加整合应激反应，而 MLIII 型小鼠上调其肾小球中的蛋白酶体系统。MLII 型和 MLIII 型均下调蛋白复合物 mTORC1（哺乳动物雷帕霉素靶蛋白复合物 1）信号转导，从而减少蛋白质合成。
严重的溶酶体功能障碍导致一些黏脂贮积症患者出现微量白蛋白尿。小鼠模型表明，在 MLII 型和 MLIII 型中存在不同的代偿途径来平衡蛋白质稳态。
