Rinschen, Markus M., Hoppe, Ann-Kathrin, Grahammer, Florian, Kann, Martin, Voelker, Linus A., Schurek, Eva-Maria, Binz, Julie, Hoehne, Martin, Demir, Fatih ORCID: 0000-0002-5744-0205, Malisic, Milena, Huber, Tobias B. ORCID: 0000-0001-7175-5062, Kurschat, Christine, Kizhakkedathu, Jayachandran N., Schermer, Bernhard ORCID: 0000-0002-5194-9000, Huesgen, Pitter F. and Benzing, Thomas (2017). N-Degradomic Analysis Reveals a Proteolytic Network Processing the Podocyte Cytoskeleton. J. Am. Soc. Nephrol., 28 (10). S. 2867 - 2879. WASHINGTON: AMER SOC NEPHROLOGY. ISSN 1533-3450

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Abstract

Regulated intracellular proteostasis, controlled in part by proteolysis, is essential in maintaining the integrity of podocytes and the glomerular filtration barrier of the kidney. We applied a novel proteomics technology that enables proteome-wide identification, mapping, and quantification of protein N-termini to comprehensively characterize cleaved podocyte proteins in the glomerulus in vivo. We found evidence that defined proteolytic cleavage results in various proteoforms of important podocyte proteins, including those of podocin, nephrin, neph1, alpha-actinin-4, and vimentin. Quantitative mapping of N-termini demonstrated perturbation of protease action during podocyte injury in vitro, including diminished proteolysis of a-actinin-4. Differentially regulated protease substrates comprised cytoskeletal proteins as well as intermediate filaments. Determination of preferential protease motifs during podocyte damage indicated activation of caspase proteases and inhibition of arginine-specific proteases. Several proteolytic processes were clearly site-specific, were conserved across species, and could be confirmed by differential migration behavior of protein fragments in gel electrophoresis. Some of the proteolytic changes discovered in vitro also occurred in two in vivo models of podocyte damage (WT1 heterozygous knockout mice and puromycin aminonucleoside treated rats). Thus, we provide direct and systems-level evidence that the slit diaphragm and podocyte cytoskeleton are regulated targets of proteolytic modification, which is altered upon podocyte damage.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Rinschen, Markus M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoppe, Ann-KathrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grahammer, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kann, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Voelker, Linus A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schurek, Eva-MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Binz, JulieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoehne, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Demir, FatihUNSPECIFIEDorcid.org/0000-0002-5744-0205UNSPECIFIED
Malisic, MilenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huber, Tobias B.UNSPECIFIEDorcid.org/0000-0001-7175-5062UNSPECIFIED
Kurschat, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kizhakkedathu, Jayachandran N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schermer, BernhardUNSPECIFIEDorcid.org/0000-0002-5194-9000UNSPECIFIED
Huesgen, Pitter F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benzing, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-216806
DOI: 10.1681/ASN.2016101119
Journal or Publication Title: J. Am. Soc. Nephrol.
Volume: 28
Number: 10
Page Range: S. 2867 - 2879
Date: 2017
Publisher: AMER SOC NEPHROLOGY
Place of Publication: WASHINGTON
ISSN: 1533-3450
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
RESISTANT NEPHROTIC SYNDROME; FOCAL SEGMENTAL GLOMERULOSCLEROSIS; KIDNEY FILTRATION BARRIER; PHOSPHOPROTEOMIC ANALYSIS; GLOMERULAR PROTEIN; DISEASE; PROTEOMICS; MUTATIONS; TERMINI; NEPHRINMultiple languages
Urology & NephrologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/21680

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