Slit diaphragm maintenance requires dynamic clathrin-mediated endocytosis facilitated by AP-2, Lap, Aux and Hsc70-4 in nephrocytes

Cell & Bioscience

Joyce van de Leemput¹  Pei Wen¹  Zhe Han¹  Zhanzheng Zhao²  Luyao Wang³ 

[1] Center for Precision Disease Modeling, Department of Medicine, University of Maryland School of Medicine, 670 West Baltimore Street, 21201, Baltimore, MD, USA;Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, 21201, Baltimore, MD, USA;Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Eastern Road, 450052, Zhengzhou, Henan, China;Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Eastern Road, 450052, Zhengzhou, Henan, China;Center for Precision Disease Modeling, Department of Medicine, University of Maryland School of Medicine, 670 West Baltimore Street, 21201, Baltimore, MD, USA;Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, 21201, Baltimore, MD, USA;

关键词: Drosophila;    Nephrocyte;    Slit diaphragm;    Endocytosis;    Clathrin;    Shi;    AP-2 complex;    Lap;    Auxilin;    Hsc70-4;   

DOI  :  10.1186/s13578-021-00595-4

来源: Springer

【 摘 要 】

BackgroundThe Slit diaphragm (SD) is the key filtration structure in human glomerular kidney that is affected in many types of renal diseases. SD proteins are known to undergo endocytosis and recycling to maintain the integrity of the filtration structure. However, the key components of this pathway remain unclear.MethodsUsing the Drosophila nephrocyte as a genetic screen platform, we screened most genes involved in endocytosis and cell trafficking, and identified the key components of the cell trafficking pathway required for SD protein endocytosis and recycling.ResultsWe discovered that the SD protein endocytosis and recycling pathway contains clathrin, dynamin, AP-2 complex, like-AP180 (Lap), auxilin and Hsc70-4 (the endocytosis part) followed by Rab11 and the exocyst complex (the recycling part). Disrupting any component in this pathway led to disrupted SD on the cell surface and intracellular accumulation of mislocalized SD proteins. We also showed the first in vivo evidence of trapped SD proteins in clathrin-coated pits at the plasma membrane when this pathway is disrupted.ConclusionsAll genes in this SD protein endocytosis and recycling pathway, as well as SD proteins themselves, are highly conserved from flies to humans. Thus, our results suggest that the SD proteins in human kidney undergo the same endocytosis and recycling pathway to maintain the filtration structure, and mutations in any genes in this pathway could lead to abnormal SD and renal diseases.

【 授权许可】

CC BY