RRC ID 53234
Author Rinschen MM, Bharill P, Wu X, Kohli P, Reinert MJ, Kretz O, Saez I, Schermer B, Höhne M, Bartram MP, Aravamudhan S, Brooks BR, Vilchez D, Huber TB, Müller RU, Krüger M, Benzing T.
Title The ubiquitin ligase Ubr4 controls stability of podocin/MEC-2 supercomplexes.
Journal Hum Mol Genet
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.
Volume 25(7)
Pages 1328-44
Published 2016-4-1
DOI 10.1093/hmg/ddw016
PII ddw016
PMID 26792178
PMC PMC4787903
MeSH Animals Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / metabolism* Calmodulin-Binding Proteins / metabolism* Cytoskeletal Proteins / metabolism* Humans Intracellular Signaling Peptides and Proteins / metabolism* Kidney Glomerulus / metabolism* Male Membrane Proteins / metabolism* Mice Microtubule-Associated Proteins / metabolism* Molecular Dynamics Simulation Nephrotic Syndrome / metabolism Ubiquitin-Protein Ligases / metabolism* Ubiquitination
IF 5.101
Times Cited 28
Resource
C.elegans tm3968