Non-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis
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Non-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis. / Reichelt, Julia; Sachs, Wiebke; Frömbling, Sarah; Fehlert, Julia; Studencka-Turski, Maja; Betz, Anna; Loreth, Desiree; Blume, Lukas; Witt, Susanne; Pohl, Sandra; Brand, Johannes; Czesla, Maire; Knop, Jan; Florea, Bogdan I; Zielinski, Stephanie; Sachs, Marlies; Hoxha, Elion; Hermans-Borgmeyer, Irm; Zahner, Gunther; Wiech, Thorsten; Krüger, Elke; Meyer-Schwesinger, Catherine.
in: NAT COMMUN, Jahrgang 14, Nr. 1, 13.04.2023, S. 2114.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Non-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis
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
N1 - © 2023. The Author(s).
PY - 2023/4/13
Y1 - 2023/4/13
N2 - 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.
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.
KW - Animals
KW - Mice
KW - Glomerulonephritis, Membranous/genetics
KW - Kidney Glomerulus
KW - Podocytes
KW - Proteasome Endopeptidase Complex
KW - Ubiquitin
KW - Ubiquitin Thiolesterase/genetics
U2 - 10.1038/s41467-023-37836-8
DO - 10.1038/s41467-023-37836-8
M3 - SCORING: Journal article
C2 - 37055432
VL - 14
SP - 2114
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -