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Non-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis

Standard

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, Vol. 14, No. 1, 13.04.2023, p. 2114.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Reichelt, J, Sachs, W, Frömbling, S, Fehlert, J, Studencka-Turski, M, Betz, A, Loreth, D, Blume, L, Witt, S, Pohl, S, Brand, J, Czesla, M, Knop, J, Florea, BI, Zielinski, S, Sachs, M, Hoxha, E, Hermans-Borgmeyer, I, Zahner, G, Wiech, T, Krüger, E & Meyer-Schwesinger, C 2023, 'Non-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis', NAT COMMUN, vol. 14, no. 1, pp. 2114. https://doi.org/10.1038/s41467-023-37836-8

APA

Reichelt, J., Sachs, W., Frömbling, S., Fehlert, J., Studencka-Turski, M., Betz, A., Loreth, D., Blume, L., Witt, S., Pohl, S., Brand, J., Czesla, M., Knop, J., Florea, B. I., Zielinski, S., Sachs, M., Hoxha, E., Hermans-Borgmeyer, I., Zahner, G., ... Meyer-Schwesinger, C. (2023). Non-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis. NAT COMMUN, 14(1), 2114. https://doi.org/10.1038/s41467-023-37836-8

Vancouver

Reichelt J, Sachs W, Frömbling S, Fehlert J, Studencka-Turski M, Betz A et al. Non-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis. NAT COMMUN. 2023 Apr 13;14(1):2114. https://doi.org/10.1038/s41467-023-37836-8

Bibtex

@article{cb4a5cf0c60942b19e776bf2d06e2fa1,
title = "Non-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis",
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.",
keywords = "Animals, Mice, Glomerulonephritis, Membranous/genetics, Kidney Glomerulus, Podocytes, Proteasome Endopeptidase Complex, Ubiquitin, Ubiquitin Thiolesterase/genetics",
author = "Julia Reichelt and Wiebke Sachs and Sarah Fr{\"o}mbling and Julia Fehlert and Maja Studencka-Turski and Anna Betz and Desiree Loreth and Lukas Blume and Susanne Witt and Sandra Pohl and Johannes Brand and Maire Czesla and Jan Knop and Florea, {Bogdan I} and Stephanie Zielinski and Marlies Sachs and Elion Hoxha and Irm Hermans-Borgmeyer and Gunther Zahner and Thorsten Wiech and Elke Kr{\"u}ger and Catherine Meyer-Schwesinger",
note = "{\textcopyright} 2023. The Author(s).",
year = "2023",
month = apr,
day = "13",
doi = "10.1038/s41467-023-37836-8",
language = "English",
volume = "14",
pages = "2114",
journal = "NAT COMMUN",
issn = "2041-1723",
publisher = "NATURE PUBLISHING GROUP",
number = "1",

}

RIS

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 -