Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Rinschen, Markus M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoppe, Ann-Kathrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Grahammer, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Kann, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Voelker, Linus A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schurek, Eva-Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Binz, Julie UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoehne, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Demir, Fatih UNSPECIFIED orcid.org/0000-0002-5744-0205 UNSPECIFIED Malisic, Milena UNSPECIFIED UNSPECIFIED UNSPECIFIED Huber, Tobias B. UNSPECIFIED orcid.org/0000-0001-7175-5062 UNSPECIFIED Kurschat, Christine UNSPECIFIED UNSPECIFIED UNSPECIFIED Kizhakkedathu, Jayachandran N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schermer, Bernhard UNSPECIFIED orcid.org/0000-0002-5194-9000 UNSPECIFIED Huesgen, Pitter F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Benzing, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language RESISTANT NEPHROTIC SYNDROME; FOCAL SEGMENTAL GLOMERULOSCLEROSIS; KIDNEY FILTRATION BARRIER; PHOSPHOPROTEOMIC ANALYSIS; GLOMERULAR PROTEIN; DISEASE; PROTEOMICS; MUTATIONS; TERMINI; NEPHRIN Multiple languages Urology & Nephrology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21680