Selective endocytosis controls slit diaphragm maintenance and dynamics in Drosophila nephrocytes

Public Deposited
Analytics

Downloadable Content

Download PDF
Request Version for Screen Reader
Creator
  • Lang, Konrad
    • Other Affiliation: University of Freiburg
  • Milosavljevic, Julian
    • Other Affiliation: University of Freiburg
  • Heinkele, Helena
    • Other Affiliation: University of Freiburg
  • Chen, Mengmeng
    • Other Affiliation: University of Freiburg
  • Gerstner, Lea
    • Other Affiliation: University of Freiburg
  • Spitz, Dominik
    • Other Affiliation: University of Freiburg
  • Kayser, Severine
    • Other Affiliation: University of Freiburg
  • Helmstädter, Martin
    • Other Affiliation: University of Freiburg
  • Walz, Gerd
    • Other Affiliation: University of Freiburg
  • Köttgen, Michael
    • Other Affiliation: University of Freiburg
  • Spracklen, Andrew
    • N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Poulton, John
    • School of Medicine, Department of Medicine
  • Hermle, Tobias
    • Other Affiliation: University of Freiburg
Abstract
  • The kidneys generate about 180 liters of primary urine per day by filtration of plasma. An essential part of the filtration barrier is the slit diaphragm, a multiprotein complex containing nephrin as major component. Filter dysfunction typically manifests with proteinuria and mutations in endocytosis regulating genes were discovered as causes of proteinuria. However, it is unclear how endocytosis regulates the slit diaphragm and how the filtration barrier is maintained without either protein leakage or filter clogging. Here we study nephrin dynamics in podocyte-like nephrocytes of Drosophila and show that selective endocytosis either by dynamin- or flotillin-mediated pathways regulates a stable yet highly dynamic architecture. Short-term manipulation of endocytic functions indicates that dynamin-mediated endocytosis of ectopic nephrin restricts slit diaphragm formation spatially while flotillin-mediated turnover of nephrin within the slit diaphragm is needed to maintain filter permeability by shedding of molecules bound to nephrin in endosomes. Since slit diaphragms cannot be studied in vitro and are poorly accessible in mouse models, this is the first analysis of their dynamics within the slit diaphragm multiprotein complex. Identification of the mechanisms of slit diaphragm maintenance will help to develop novel therapies for proteinuric renal diseases that are frequently limited to symptomatic treatment.
Date of publication
DOI
Identifier
Resource type
  • Article
Rights statement
  • In Copyright
Journal title
  • eLife
Journal volume
  • 11
Page start
  • e79037
Language
  • English
Version
  • Postprint
ISSN
  • 2050-084X

Relations

Parents:

This work has no parents.

In Collection:

Items

Thumbnail Title Date Uploaded Visibility Actions
file details elife-79037-v1.pdf 2022-08-02 Public Download