Structural mechanism of Roquin-RNA interactions linked to autoimmunity

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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.