TY  - JOUR
AU  - Reichelt, Julia
AU  - Sachs, Wiebke
AU  - Frömbling, Sarah
AU  - Fehlert, Julia
AU  - Studencka-Turski, Maja
AU  - Betz, Anna
AU  - Loreth, Desiree
AU  - Blume, Lukas
AU  - Witt, Susanne
AU  - Pohl, Sandra
AU  - Brand, Johannes
AU  - Czesla, Maire
AU  - Knop, Jan
AU  - Florea, Bogdan I.
AU  - Zielinski, Stephanie
AU  - Sachs, Marlies
AU  - Hoxha, Elion
AU  - Hermans-Borgmeyer, Irm
AU  - Zahner, Gunther
AU  - Wiech, Thorsten
AU  - Krüger, Elke
AU  - Meyer-Schwesinger, Catherine
TI  - Non-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis
JO  - Nature Communications
VL  - 14
IS  - 1
SN  - 2041-1723
CY  - London
PB  - Nature Publishing Group UK
M1  - PUBDB-2023-07626
SP  - 2114
PY  - 2023
N1  - 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.
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:37055432
UR  - <Go to ISI:>//WOS:000978473800001
DO  - DOI:10.1038/s41467-023-37836-8
UR  - https://bib-pubdb1.desy.de/record/599937
ER  -