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

Rinschen, M. M., Bharill, P., Wu, X., Kohli, P., Reinert, M. J., Kretz, O., et al. (2016). The ubiquitin ligase Ubr4 controls stability of podocin/MEC-2 supercomplexes. HUMAN MOLECULAR GENETICS, 25(7), 1328-1344. doi:10.1093/hmg/ddw016.

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 Creators:
Rinschen, Markus M., Author
Bharill, Puneet, Author
Wu, Xiongwu, Author
Kohli, Priyanka, Author
Reinert, Matthaeus J., Author
Kretz, Oliver, Author
Saez, Isabel, Author
Schermer, Bernhard, Author
Hoehne, Martin, Author
Bartram, Malte P., Author
Aravamudhan, Sriram1, Author              
Brooks, Bernard R., Author
Vilchez, David, Author
Huber, Tobias B., Author
Mueller, Roman-Ulrich, Author
Krüger, Marcus2, Author              
Benzing, Thomas, Author
Affiliations:
1Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591695              
2Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591698              

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Free keywords: RESISTANT NEPHROTIC SYNDROME; KIDNEY FILTRATION BARRIER; CAENORHABDITIS-ELEGANS; C-ELEGANS; PROTEOMIC ANALYSIS; SLIT DIAPHRAGM; SWISS-MODEL; POSTTRANSLATIONAL MODIFICATIONS; GLOMERULAR PODOCYTE; MASS-SPECTROMETRYBiochemistry & Molecular Biology; Genetics & Heredity;
 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.

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Language(s): eng - English
 Dates: 2016
 Publication Status: Published in print
 Pages: 17
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000374231000007
DOI: 10.1093/hmg/ddw016
 Degree: -

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Title: HUMAN MOLECULAR GENETICS
Source Genre: Journal
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Publ. Info: GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND : OXFORD UNIV PRESS
Pages: - Volume / Issue: 25 (7) Sequence Number: - Start / End Page: 1328 - 1344 Identifier: ISSN: 0964-6906