%0 Journal Article
%A Breitkopf, Daniel M
%A Jankowski, Vera
%A Ohl, Kim
%A Hermann, Juliane
%A Hermert, Daniela
%A Tenbrock, Klaus
%A Liu, Xiyang
%A Martin, Ina V
%A Wang, Jialin
%A Groll, Fabian
%A Gröne, Elisabeth
%A Floege, Jürgen
%A Ostendorf, Tammo
%A Rauen, Thomas
%A Raffetseder, Ute
%T The YB-1:Notch-3 axis modulates immune cell responses and organ damage in systemic lupus erythematosus.
%J Kidney international
%V 97
%N 2
%@ 0085-2538
%C New York, NY
%I Elsevier
%M DKFZ-2020-00035
%P 289-303
%D 2020
%Z 2020 Feb;97(2):289-303
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:31882173
%R 10.1016/j.kint.2019.09.031
%U https://inrepo02.dkfz.de/record/148843