Structural mechanism of Roquin-RNA interactions linked to autoimmunity

自身免疫性疾病仍然是现代文明的一大挑战。尽管在过去的一个世纪里，许多由入侵病原体引起的灾难性感染得到了遏制，但越来越多的患者患有自身免疫性疾病和/或对变应原过敏。了解自身免疫反应的分子机制是成功和特异治疗的关键。免疫反应的重要作用归因于T细胞共刺激受体。本研究旨在揭示RNA结合蛋白Roquin抑制可诱导T细胞共刺激表面受体(ICOS)的分子细节。目前已知ICOS的表达受转录后调控，其机制尚不清楚。Roquin调查了ICOS mRNA，调节失调是系统性自身免疫的主要原因，已知的红斑狼疮症状主要表现为结缔组织的破坏。除了ICOS，这项拟议的研究还将包括其他已被很好描述的Roquin mRNA靶点，如OX40和TNF-α，以从结构水平上研究各自的细胞表面受体的抑制。Roquin的分子功能和三维结构在很大程度上尚不清楚。因此，本研究旨在研究Roquin的结构细节，它与ICOS-和其他mRNAs的结合，并最终招募辅助因子。Roquin包括环状和锌指结构域，以及RNA结合所需的一个新的结构域，称为ROQ。本研究旨在揭示ROQ结构域与RNA结合的结构细节，并从mRNA水平阐明免疫调节的分子机制。这项研究将侧重于实验结构生物学，使用核磁共振(核磁共振)光谱和X射线结晶学、生化和生物物理研究来表征分子相互作用并结合功能分析(在合作中)。研究Roquin与ICOS-和其他mRNAs的复合体的结构有望揭示自身免疫的分子机制，这将对在mRNA水平上的免疫调节具有更广泛的意义。

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.