Institute of Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Hamburg, Germany.
Nat Commun. 2023 Apr 13;14(1):2114. doi: 10.1038/s41467-023-37836-8.
Little is known about the mechanistic significance of the ubiquitin proteasome system (UPS) in a kidney autoimmune environment. In membranous nephropathy (MN), autoantibodies target podocytes of the glomerular filter resulting in proteinuria. Converging biochemical, structural, mouse pathomechanistic, and clinical information we report that the deubiquitinase Ubiquitin C-terminal hydrolase L1 (UCH-L1) is induced by oxidative stress in podocytes and is directly involved in proteasome substrate accumulation. Mechanistically, this toxic gain-of-function is mediated by non-functional UCH-L1, which interacts with and thereby impairs proteasomes. In experimental MN, UCH-L1 becomes non-functional and MN patients with poor outcome exhibit autoantibodies with preferential reactivity to non-functional UCH-L1. Podocyte-specific deletion of UCH-L1 protects from experimental MN, whereas overexpression of non-functional UCH-L1 impairs podocyte proteostasis and drives injury in mice. In conclusion, the UPS is pathomechanistically linked to podocyte disease by aberrant proteasomal interactions of non-functional UCH-L1.
关于泛素蛋白酶体系统（UPS）在肾脏自身免疫环境中的机制意义知之甚少。在膜性肾病（MN）中，自身抗体针对肾小球滤过器的足细胞，导致蛋白尿。我们汇集了生化、结构、小鼠发病机制和临床信息，报告说泛素 C 端水解酶 L1（UCH-L1）在足细胞中由氧化应激诱导，并且直接参与蛋白酶体底物的积累。从机制上讲，这种毒性获得性功能是由非功能 UCH-L1 介导的，它与蛋白酶体相互作用并因此损害蛋白酶体。在实验性 MN 中，UCH-L1 失去功能，预后不良的 MN 患者表现出对非功能 UCH-L1 具有优先反应性的自身抗体。足细胞特异性敲除 UCH-L1 可预防实验性 MN，而过表达非功能 UCH-L1 则会损害足细胞蛋白稳态并导致小鼠损伤。总之，UPS 通过异常的非功能 UCH-L1 与蛋白酶体相互作用与足细胞疾病发病机制相关。
