The proteasome modulates endocytosis specifically in glomerular cells to promote kidney filtration.
The proteasome modulates endocytosis specifically in glomerular cells to promote kidney filtration.
复制标题
蛋白酶体专门调节肾小球细胞中的内吞作用，以促进肾脏滤过。
DOI：
10.1038/s41467-024-46273-0
复制
发表时间：
2024
影响因子：
16.6
通讯作者：
Kr
中科院分区：
文献类型：
--
作者：
Sachs,Wiebke;Blume,Lukas;Loreth,Desiree;Schebsdat,Lisa;Hatje,Favian;Koehler,Sybille;Wedekind,Uta;Sachs,Marlies;Zieliniski,Stephanie;Brand,Johannes;Conze,Christian;Florea,BogdanI;Heppner,Frank;Krüger,Elke;Rinschen,MarkusM;Kr
肾滤过是由足细胞、内皮细胞和系膜细胞的相互作用保证的。免疫球蛋白在滤过屏障处积聚是肾小球损伤的典型症状。调节滤膜渗透性的机制尚不清楚。在这里，我们确定了蛋白酶体在特定细胞类型中的关键作用。结合遗传和基于抑制剂的人、猪、小鼠和果蝇模型，我们证明蛋白酶体维持滤过屏障的完整性，足细胞需要组成性和肾小球内皮细胞的免疫蛋白酶体活性。内皮免疫蛋白酶体缺乏和蛋白酶体抑制破坏小鼠的滤过屏障，导致病理性免疫球蛋白沉积。在机制上，我们观察到内吞活性降低，导致膜循环和内吞受体转换改变。这项工作扩展了（免疫）蛋白酶体作为调控蛋白质降解、抗原呈递和内吞作用的控制蛋白酶的概念，为治疗疾病相关的肾小球蛋白积累提供了新的治疗靶点。
Kidney filtration is ensured by the interaction of podocytes, endothelial and mesangial cells. Immunoglobulin accumulation at the filtration barrier is pathognomonic for glomerular injury. The mechanisms that regulate filter permeability are unknown. Here, we identify a pivotal role for the proteasome in a specific cell type. Combining genetic and inhibitor-based human, pig, mouse, andDrosophilamodels we demonstrate that the proteasome maintains filtration barrier integrity, with podocytes requiring the constitutive and glomerular endothelial cells the immunoproteasomal activity. Endothelial immunoproteasome deficiency as well as proteasome inhibition disrupt the filtration barrier in mice, resulting in pathologic immunoglobulin deposition. Mechanistically, we observe reduced endocytic activity, which leads to altered membrane recycling and endocytic receptor turnover. This work expands the concept of the (immuno)proteasome as a control protease orchestrating protein degradation and antigen presentation and endocytosis, providing new therapeutic targets to treat disease-associated glomerular protein accumulations.