학술논문
Non-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis
Document Type
article
Author
Julia Reichelt; Wiebke Sachs; Sarah Frömbling; Julia Fehlert; Maja Studencka-Turski; Anna Betz; Desiree Loreth; Lukas Blume; Susanne Witt; Sandra Pohl; Johannes Brand; Maire Czesla; Jan Knop; Bogdan I. Florea; Stephanie Zielinski; Marlies Sachs; Elion Hoxha; Irm Hermans-Borgmeyer; Gunther Zahner; Thorsten Wiech; Elke Krüger; Catherine Meyer-Schwesinger
Source
Nature Communications, Vol 14, Iss 1, Pp 1-19 (2023)
Subject
Language
English
ISSN
2041-1723
Abstract
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.