Reference - Detail
| 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 Prohibitins Ubiquitin-Protein Ligases / metabolism* Ubiquitination |
| IF | 5.101 |
| Times Cited | 28 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | News |
| Total number of mentions | 2 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| C.elegans | tm3968 |