Structural mechanism of Roquin-RNA interactions linked to autoimmunity

自身免疫性疾病仍然对现代文明构成重大挑战。虽然在过去的世纪中，由入侵病原体引起的许多灾难性感染已经被遏制，但越来越多的患者患有自身免疫性疾病和/或对过敏原的超敏反应。了解自身免疫反应的分子机制是成功和特异性治疗的关键方法。免疫应答的重要作用归因于T细胞共刺激受体。本研究的目的是揭示RNA结合蛋白Roquin抑制诱导型T细胞共刺激表面受体（ICOS）的分子细节。已知ICOS的表达受迄今未知机制的转录后调控。ICOS mRNA由Roquin调查，调节异常是系统性自身免疫的主要原因，具有已知的红斑狼疮症状，主要通过结缔组织破坏显示。除了ICOS，拟议的研究将包括其他描述良好的Roquin mRNA靶点，如Ox 40和TNF-α，以研究在结构水平上抑制相应的细胞表面受体。Roquin的分子功能和三维结构在很大程度上是未知的。因此，本研究旨在研究Roquin的结构细节，其与ICOS和其他mRNA的结合，并最终招募辅助因子。Roquin包含RING和锌指结构域以及RNA结合所需的称为ROQ的新结构域。拟议的研究旨在揭示ROQ结构域与RNA结合的结构细节，并阐明mRNA水平调节免疫反应的分子机制。该研究将侧重于实验结构生物学，使用核磁共振（NMR）光谱学和X射线晶体学，生物化学和生物物理研究来表征分子相互作用与功能分析（合作）。研究Roquin与ICOS和其他mRNA复合的结构有望揭示自身免疫的分子机制，这将对mRNA水平的免疫调节产生更广泛的影响。

Autoimmune diseases still pose a major challenge to modern civilizations. While many disastrous infections, caused by invading pathogens, have been contained during the past century, a growing number of patients suffer from autoimmune diseases and/or hypersensitivity against allergens. Understanding molecular mechanisms of autoimmune reactions is a key approach towards successful and specific treatment. An important role for the immune response is ascribed to T-cell co-stimulatory receptors. This study, exemplarily, aims at revealing the molecular details of the repression of the inducible T cell co-stimulatory surface receptor (ICOS) by the RNA binding protein Roquin. The expression of ICOS is known to be regulated post-transcriptionally by so far unknown mechanisms. ICOS mRNA is surveyed by Roquin and dysregulation is a major cause for systemic autoimmunity with symptoms known from Lupus Erythematosus, mainly displayed through the destruction of connective tissue. Besides ICOS, the proposed study will include additional well-described Roquin mRNA targets like Ox40 and TNF-alpha to also investigate the suppression of respective cell surface receptors on the structural level.Molecular functions and the three-dimensional structure of Roquin are largely unknown. This study therefore aims at investigating structural details of Roquin, its binding to the ICOS- and other mRNAs, and eventually the recruitment of co-factors. Roquin comprises RING and zinc finger domains and a novel domain, termed ROQ, which is required for RNA binding. The proposed research aims at revealing the structural details of RNA binding by the ROQ domain and elucidating molecular mechanisms of the regulation of immune responses at the level of mRNA. The research will focus on experimental structural biology, using nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography, biochemical and biophysical studies to characterize the molecular interactions combined with functional analysis (in collaboration). Examining Roquin's structure in complex with ICOS- and other mRNAs is expected to reveal a molecular mechanism of autoimmunity that will have more general implications for the regulation of immunity at the level of mRNA.