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

系统性红斑狼疮(SLE)是一种自身免疫性疾病，实际上可能会影响到每个器官系统。尤其是肾脏受累患者(狼疮性肾炎，LN)仍表现出较高的发病率和病死率。我们自己的结果显示，受体蛋白Notch-3在LN患者的肾小球和狼疮易感小鼠的肾脏中的表达显著增加。Noch-3信号通过膜结合的(典型的)和可溶性的配体激活，包括Y-box结合蛋白(Yb)-1。通过质谱仪，我们在SLE患者的血清中检测到YB-1(YB-1-2G)高度保守的冷休克结构域中两个赖氨酸残基上的特异性愈创木酚化。这些修饰在活动期SLE患者和LN患者中尤其存在，并诱导了显著的Notch-3激活。我们证明了在狼疮发展过程中Notch-3的激活提供了一些保护作用，而遗传Notch-3的缺失则加重了几种狼疮的表现。根据目前的建议，我们的目的是分析YB-1愈创木酚化的分子机制和改变的功能后果，并澄清这种修饰是否影响NOCH-3信号转导。此外，我们还研究了胍化的潜在(酶)机制及其抗原潜力，并将加强我们在SLE患者队列中YB-1-2G存在与疾病活动指数(SLEDAI/BILAG)关联的关键结果。

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.