Journal Article

PUBDB-2023-07626

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Non-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis

Reichelt, J. ; Sachs, W. ; Frömbling, S. ; Fehlert, J. ; Studencka-Turski, M. ; Betz, A. ; Loreth, D. ; Blume, L. ; Witt, S.CSSB*DESY* ; Pohl, S. ; Brand, J. ; Czesla, M. ; Knop, J.Extern*EMBL* ; Florea, B. I. ; Zielinski, S. ; Sachs, M. ; Hoxha, E. ; Hermans-Borgmeyer, I. ; Zahner, G. ; Wiech, T. ; Krüger, E. ; Meyer-Schwesinger, C. (Corresponding author)

2023
Nature Publishing Group UK London

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Please use a persistent id in citations: doi:10.1038/s41467-023-37836-8  doi:10.3204/PUBDB-2023-07626

Abstract: Little is known about the mechanistic significance of the ubiquitin proteasome system (UPS) in a kidney autoimmune environment. In membranous nephropathy (MN), autoantibodies target podocytes of the glomerular filter resulting in proteinuria. Converging biochemical, structural, mouse pathomechanistic, and clinical information we report that the deubiquitinase Ubiquitin C-terminal hydrolase L1 (UCH-L1) is induced by oxidative stress in podocytes and is directly involved in proteasome substrate accumulation. Mechanistically, this toxic gain-of-function is mediated by non-functional UCH-L1, which interacts with and thereby impairs proteasomes. In experimental MN, UCH-L1 becomes non-functional and MN patients with poor outcome exhibit autoantibodies with preferential reactivity to non-functional UCH-L1. Podocyte-specific deletion of UCH-L1 protects from experimental MN, whereas overexpression of non-functional UCH-L1 impairs podocyte proteostasis and drives injury in mice. In conclusion, the UPS is pathomechanistically linked to podocyte disease by aberrant proteasomal interactions of non-functional UCH-L1.

Note: The authors would like to thank Antonio Virgillio Failla from the UMIF,UKE and Roland Thuenauer from the ALFM, CSSB, DESY for technicalassistance in super resolution microscopy.

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Contributing Institute(s):

1. Strukturelle Mikrobiologie CSSB (FS-CS)
2. CSSB - Core Facility - Protein Production (CSSB-CF-PP)

Research Program(s):

1. 633 - Life Sciences – Building Blocks of Life: Structure and Function (POF4-633) (POF4-633)

Experiment(s):

1. No specific instrument

Appears in the scientific report 2023

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Linked articles:

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Journal Article Reichelt, J. ; Sachs, W. ; Frömbling, S. ; Fehlert, J. ; Studencka-Turski, M. ; Betz, A. ; Loreth, D. ; Blume, L. ; Witt, S.Extern*CSSB*DESY* ; Pohl, S. ; Brand, J. ; Czesla, M. ; Knop, J.Extern*EMBL* ; Florea, B. I. ; Zielinski, S. ; Sachs, M. ; Hoxha, E. ; Hermans-Borgmeyer, I. ; Zahner, G. ; Wiech, T. ; Krüger, E. ; Meyer-Schwesinger, C. (Corresponding author)
Publisher Correction: Non-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis
Nature Communications 14(1), 2453 (2023) [10.1038/s41467-023-38206-0]2023     Files BibTeX | EndNote: XML, Text | RIS

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