以 TMED 货物受体为靶标可挽救中断的尿囊素贩运。

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Silvana Bazua-Valenti, Matthew R Brown, Jason Zavras, Magdalena Riedl Khursigara, Elizabeth Grinkevich, Eriene-Heidi Sidhom, Keith H Keller, Matthew Racette, Moran Dvela-Levitt, Catarina Quintanova, Hasan Demirci, Sebastian Sewerin, Alissa C Goss, John Lin, Hyery Yoo, Alvaro S Vaca Jacome, Malvina Papanastasiou, Namrata Udeshi, Steven A Carr, Nina Himmerkus, Markus Bleich, Kerim Mutig, Sebastian Bachmann, Jan Halbritter, Stanislav Kmoch, Martina Živná, Kendrah Kidd, Anthony J Bleyer, Astrid Weins, Seth L Alper, Jillian L Shaw, Maria Kost-Alimova, Juan Lorenzo B Pablo, Anna Greka
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引用次数: 0

摘要

尿调蛋白(UMOD)是人类尿液中最丰富的蛋白质,其转运动态在肾脏疾病的发病机制中起着关键作用。UMOD基因的单等位基因突变导致常染色体显性小管间质肾病(ADTKD-UMOD),这是一种无法治愈的遗传性疾病,可导致肾衰竭。这种疾病是由突变的UMOD在肾上皮细胞内的细胞内包裹引起的,但介导UMOD运输中断的确切机制仍然难以捉摸。在这里,我们报道了跨膜Emp24蛋白运输结构域(TMED)货物受体TMED2, TMED9和TMED10结合UMOD并调节其沿分泌途径的运输。在细胞、ADTKD-UMOD患者衍生的人肾类器官和UMOD敲入突变的小鼠中靶向tmed可减少突变型UMOD在细胞内的积累,恢复UMOD在根尖质膜的运输和定位。在体内,tmed靶向的小分子也减轻了内质网应激和肾脏损伤和纤维化的标志物。我们的工作揭示了tmed靶向小分子作为一种有前途的治疗肾蛋白病的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Disrupted uromodulin trafficking is rescued by targeting TMED cargo receptors.

The trafficking dynamics of uromodulin (UMOD), the most abundant protein in human urine, play a critical role in the pathogenesis of kidney disease. Monoallelic mutations in the UMOD gene cause autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD), an incurable genetic disorder that leads to kidney failure. The disease is caused by the intracellular entrapment of mutant UMOD in kidney epithelial cells, but the precise mechanisms mediating disrupted UMOD trafficking remain elusive. Here, we report that transmembrane Emp24 protein transport domain-containing (TMED) cargo receptors TMED2, TMED9, and TMED10 bind UMOD and regulate its trafficking along the secretory pathway. Pharmacological targeting of TMEDs in cells, in human kidney organoids derived from patients with ADTKD-UMOD, and in mutant-UMOD-knockin mice reduced intracellular accumulation of mutant UMOD and restored trafficking and localization of UMOD to the apical plasma membrane. In vivo, the TMED-targeted small molecule also mitigated ER stress and markers of kidney damage and fibrosis. Our work reveals TMED-targeting small molecules as a promising therapeutic strategy for kidney proteinopathies.

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来源期刊
Journal of Clinical Investigation
Journal of Clinical Investigation 医学-医学:研究与实验
CiteScore
24.50
自引率
1.30%
发文量
1034
审稿时长
2 months
期刊介绍: The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science. The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others. The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.
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