TY  - JOUR
AU  - Breitkopf, Daniel M
AU  - Jankowski, Vera
AU  - Ohl, Kim
AU  - Hermann, Juliane
AU  - Hermert, Daniela
AU  - Tenbrock, Klaus
AU  - Liu, Xiyang
AU  - Martin, Ina V
AU  - Wang, Jialin
AU  - Groll, Fabian
AU  - Gröne, Elisabeth
AU  - Floege, Jürgen
AU  - Ostendorf, Tammo
AU  - Rauen, Thomas
AU  - Raffetseder, Ute
TI  - The YB-1:Notch-3 axis modulates immune cell responses and organ damage in systemic lupus erythematosus.
JO  - Kidney international
VL  - 97
IS  - 2
SN  - 0085-2538
CY  - New York, NY
PB  - Elsevier
M1  - DKFZ-2020-00035
SP  - 289-303
PY  - 2020
N1  - 2020 Feb;97(2):289-303
AB  - Systemic lupus erythematosus (SLE) is an autoimmune disease and lupus nephritis is a major risk factor for morbidity and mortality. Notch-3 signaling induced by membrane-bound or soluble ligands such as YB-1 constitutes an evolutionarily conserved pathway that determines major decisions in cell fate. Mass spectrometry of extracellular YB-1 in sera from patients with SLE and lupus-prone mice revealed specific post-translational guanidinylation of two lysine residues within the highly conserved cold-shock domain of YB-1 (YB-1-G). These modifications highly correlated with SLE disease activity, especially in patients with lupus nephritis and resulted in enhanced activation of Notch-3 signaling in T lymphocytes. The importance of YB-1:Notch-3 interaction in T cells was further evidenced by increased interleukin (Il)10 expression following YB-1-G stimulation and detection of both, YB-1-G and Notch-3, in kidneys of MRL.lpr mice by mass spectrometry imaging. Notch-3 expression and activation was significantly up-regulated in kidneys of 20-week-old MRL.lpr mice. Notably, lupus-prone mice with constitutional Notch-3 depletion (B6.Faslpr/lprNotch3-/-) exhibited an aggravated lupus phenotype with significantly increased mortality, enlarged lymphoid organs and aggravated nephritis. Additionally, these mice displayed fewer regulatory T cells and reduced amounts of anti-inflammatory IL-10. Thus, our results indicate that the YB-1:Notch-3 axis exerts protective effects in SLE and that Notch-3 deficiency exacerbates the SLE phenotype.
LB  - PUB:(DE-HGF)16
C6  - pmid:31882173
DO  - DOI:10.1016/j.kint.2019.09.031
UR  - https://inrepo02.dkfz.de/record/148843
ER  -