Notch-3 and a posttranslational modification of Y-box binding protein 1 alter the immune cell balance and the pathophysiology in systemic lupus erythematosus

Breitkopf, Daniel; Raffetseder, Ute (Thesis advisor); Panstruga, Ralph (Thesis advisor)

Aachen (2020)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2020

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease that might affect all major organ systems and often involves the kidneys. Kidney inflammation, called lupus nephritis (LN), is the major cause of morbidity and mortality in patients that suffer from SLE. The transmembrane receptor Notch-3 and its non-canonical soluble ligand Y-box binding protein-1 (YB-1) have been shown to be upregulated in glomeruli of SLE patients, and their in-teraction has been analyzed in this doctoral thesis on gene and protein level using different lupus-prone mouse strains, and cell culture models. A posttranslational modification (guanidinylation) of the lysine residues 53 and 58 of YB-1 has been found exclusively in sera from active LN patients and lupus mice, and these modifications led to an elevated signaling via Notch-3 in vitro. In SLE, Notch-3 is mainly found in parietal cells located at the Bowman’s capsule in glomeruli. In the course of SLE, Notch-3 levels are upregulated, which is considered beneficial for lupus progression. This statement is based on the finding that knockdown/knockout of Notch3 in lupus-prone lpr mice led to a more severe phenotype with organomegalies and changed immune cell status with low amounts of regulatory and high amounts of double negative T cells leading to a highly inflammatory environment. Also, the animals died much earlier. The experiments leading to this conclusion were performed via knockdown of Notch3 using antisense oligodeoxynucleotides in lupus-prone MRL.lpr mice, and by crossbreeding of B6.lpr with B6.Notch3-/- mice generating a B6.lpr.Notch3-/- strain.