YB-1 guanidinylation in systemic lupus erythematosus: Studies on molecular mechanisms, functional properties and its potential as biomarker

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Systemic lupus erythematosus (SLE) is an autoimmune disease that may virtually affect every organ system. Particularly patients with renal involvement (lupus nephritis, LN) still display a high morbidity and mortality. Our own results demonstrate that expression of receptor protein Notch-3 is significantly increased in glomeruli from LN patients and in kidneys from lupus-prone mice. Notch-3 signalling is activated through membrane-bound (canonical) and soluble ligands including Y-box binding protein (YB)-1. By mass spectrometry, we detected a specific guadinylation at two lysine residues within the highly conserved cold shock domain of YB-1 (YB-1-2G) in sera obtained from SLE patients. These modifications were particularly present in active SLE patients and specifically in LN patients and induced a prominent Notch-3 activation. We demonstrated that Notch-3 activation during lupus development confers a number of protective effects whereas genetic Notch-3 depletion aggravates several lupus manifestations. With the present proposal, we aim to analyze molecular mechanisms and changed functional consequences of YB-1 guadinylation and to clarify whether this modification affects Noch-3 signalling. Furthermore, the underlying (enzymatic) mechanisms of guanidinylation and their antigen potential are investigated and we will strengthen our pivotal results on the association of YB-1-2G presence and disease activity indices (SLEDAI/BILAG) in larger cohorts of SLE patients.