Schip1 is a novel podocyte foot process protein that mediates actin cytoskeleton rearrangements and forms a complex with Nherf2 and ezrin

PLoS One. 2015 Mar 25;10(3):e0122067. doi: 10.1371/journal.pone.0122067. eCollection 2015.

Abstract

Background: Podocyte foot process effacement accompanied by actin cytoskeleton rearrangements is a cardinal feature of many progressive human proteinuric diseases.

Results: By microarray profiling of mouse glomerulus, SCHIP1 emerged as one of the most highly enriched transcripts. We detected Schip1 protein in the kidney glomerulus, specifically in podocytes foot processes. Functionally, Schip1 inactivation in zebrafish by morpholino knock-down results in foot process disorganization and podocyte loss leading to proteinuria. In cultured podocytes Schip1 localizes to cortical actin-rich regions of lamellipodia, where it forms a complex with Nherf2 and ezrin, proteins known to participate in actin remodeling stimulated by PDGFβ signaling. Mechanistically, overexpression of Schip1 in vitro causes accumulation of cortical F-actin with dissolution of transversal stress fibers and promotes cell migration in response to PDGF-BB stimulation. Upon actin disassembly by latrunculin A treatment, Schip1 remains associated with the residual F-actin-containing structures, suggesting a functional connection with actin cytoskeleton possibly via its interaction partners. A similar assay with cytochalasin D points to stabilization of cortical actin cytoskeleton in Schip1 overexpressing cells by attenuation of actin depolymerisation.

Conclusions: Schip1 is a novel glomerular protein predominantly expressed in podocytes, necessary for the zebrafish pronephros development and function. Schip1 associates with the cortical actin cytoskeleton network and modulates its dynamics in response to PDGF signaling via interaction with the Nherf2/ezrin complex. Its implication in proteinuric diseases remains to be further investigated.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / drug effects
  • Actin Cytoskeleton / metabolism*
  • Actins / metabolism
  • Animals
  • Becaplermin
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Movement
  • Cells, Cultured
  • Cytochalasin D / metabolism
  • Cytoskeletal Proteins / metabolism*
  • Fluorescence Resonance Energy Transfer
  • HEK293 Cells
  • Humans
  • Kidney Glomerulus / metabolism
  • Microscopy, Fluorescence
  • Oligonucleotides, Antisense / metabolism
  • Phosphoproteins / metabolism*
  • Podocytes / cytology
  • Podocytes / metabolism*
  • Pronephros / metabolism
  • Proto-Oncogene Proteins c-sis / pharmacology
  • Pseudopodia / metabolism
  • RNA Interference
  • Signal Transduction / drug effects
  • Sodium-Hydrogen Exchangers / metabolism*
  • Thiazolidines / pharmacology
  • Zebrafish / metabolism
  • Zebrafish Proteins / antagonists & inhibitors
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*

Substances

  • Actins
  • Bridged Bicyclo Compounds, Heterocyclic
  • Carrier Proteins
  • Cytoskeletal Proteins
  • Oligonucleotides, Antisense
  • Phosphoproteins
  • Proto-Oncogene Proteins c-sis
  • SCHIP1 protein, human
  • Sodium-Hydrogen Exchangers
  • Thiazolidines
  • Zebrafish Proteins
  • ezrin
  • sodium-hydrogen exchanger regulatory factor
  • Becaplermin
  • Cytochalasin D
  • latrunculin A

Grant support

This work was supported by grants from the Knut and Alice Wallenberg Foundation (KT, CB), the Swedish Research Council (KT, CB, JP), the Swedish Foundation for Strategic Research (KT, CB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.