Format

Send to

Choose Destination
Hum Mol Genet. 2016 Apr 1;25(7):1328-44. doi: 10.1093/hmg/ddw016. Epub 2016 Jan 19.

The ubiquitin ligase Ubr4 controls stability of podocin/MEC-2 supercomplexes.

Author information

1
Department II of Internal Medicine, Center for Molecular Medicine Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol), University of Cologne, Cologne, Germany, markus.rinschen@uk-koeln.de thomas.benzing@uk-koeln.de.
2
Department II of Internal Medicine, Systems Biology of Ageing Cologne (Sybacol), University of Cologne, Cologne, Germany.
3
Laboratory of Computational Biology, National Heart, Blood, and Lung Institute, National Institutes of Health, Bethesda, MD 20892, USA.
4
Department II of Internal Medicine, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and.
5
Department II of Internal Medicine.
6
Renal Division, University Hospital Freiburg, Freiburg, Germany, Neuroanatomy, University of Freiburg, Freiburg, Germany.
7
Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and.
8
Department II of Internal Medicine, Center for Molecular Medicine Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol), University of Cologne, Cologne, Germany.
9
Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany and.
10
Renal Division, University Hospital Freiburg, Freiburg, Germany, BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
11
Center for Molecular Medicine Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and.

Abstract

The PHB-domain protein podocin maintains the renal filtration barrier and its mutation is an important cause of hereditary nephrotic syndrome. Podocin and its Caenorhabditis elegans orthologue MEC-2 have emerged as key components of mechanosensitive membrane protein signalling complexes. Whereas podocin resides at a specialized cell junction at the podocyte slit diaphragm, MEC-2 is found in neurons required for touch sensitivity. Here, we show that the ubiquitin ligase Ubr4 is a key component of the podocin interactome purified both from cultured podocytes and native glomeruli. It colocalizes with podocin and regulates its stability. In C. elegans, this process is conserved. Here, Ubr4 is responsible for the degradation of mislocalized MEC-2 multimers. Ubiquitylomic analysis of mouse glomeruli revealed that podocin is ubiquitylated at two lysine residues. These sites were Ubr4-dependent and were conserved across species. Molecular dynamics simulations revealed that ubiquitylation of one site, K301, do not only target podocin/MEC-2 for proteasomal degradation, but may also affect stability and disassembly of the multimeric complex. We suggest that Ubr4 is a key regulator of podocyte foot process proteostasis.

PMID:
26792178
PMCID:
PMC4787903
DOI:
10.1093/hmg/ddw016
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center