Rinschen, Markus M., Bharill, Puneet, Wu, Xiongwu, Kohli, Priyanka ORCID: 0000-0002-0651-4008, Reinert, Matthaeus J., Kretz, Oliver, Saez, Isabel, Schermer, Bernhard ORCID: 0000-0002-5194-9000, Hoehne, Martin, Bartram, Malte P., Aravamudhan, Sriram, Brooks, Bernard R., Vilchez, David ORCID: 0000-0002-0801-0743, Huber, Tobias B. ORCID: 0000-0001-7175-5062, Mueller, Roman-Ulrich, Krueger, Marcus ORCID: 0000-0003-2008-4582 and Benzing, Thomas (2016). The ubiquitin ligase Ubr4 controls stability of podocin/MEC-2 supercomplexes. Hum. Mol. Genet., 25 (7). S. 1328 - 1345. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Rinschen, Markus M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bharill, PuneetUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wu, XiongwuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kohli, PriyankaUNSPECIFIEDorcid.org/0000-0002-0651-4008UNSPECIFIED
Reinert, Matthaeus J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kretz, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saez, IsabelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schermer, BernhardUNSPECIFIEDorcid.org/0000-0002-5194-9000UNSPECIFIED
Hoehne, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartram, Malte P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aravamudhan, SriramUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brooks, Bernard R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vilchez, DavidUNSPECIFIEDorcid.org/0000-0002-0801-0743UNSPECIFIED
Huber, Tobias B.UNSPECIFIEDorcid.org/0000-0001-7175-5062UNSPECIFIED
Mueller, Roman-UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, MarcusUNSPECIFIEDorcid.org/0000-0003-2008-4582UNSPECIFIED
Benzing, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-279791
DOI: 10.1093/hmg/ddw016
Journal or Publication Title: Hum. Mol. Genet.
Volume: 25
Number: 7
Page Range: S. 1328 - 1345
Date: 2016
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2083
Language: English
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PROTEOMIC ANALYSIS; SWISS-MODEL; N-RECOGNIN; PROTEIN; PODOCYTE; GENE; REVEALS; NEPHRIN; MEC-2; UBIQUITYLATIONMultiple languages
Biochemistry & Molecular Biology; Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/27979

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