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Investigation of a translational control mechanism activated by interleukin 1

白细胞介素1激活的翻译控制机制的研究

基本信息

批准号：
187087359
负责人：
Professor Dr. Helmut Holtmann
金额：
--
依托单位：
Zentrum Biochemie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2010
资助国家：
德国
起止时间：
2009-12-31 至 2016-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/187087359?language=en
关键词：
Investigation translational control mechanism activated

项目摘要

The pro-inflammatory cytokine IL-1 activates post-transcriptional mechanisms that contribute to the expression of proteins involved in immune and inflammatory reactions. Information obtained in the first funding period indicates that IL-1 increases translation of two distinct groups of mRNAs by counteracting translational silencing mechanisms. One group, represented by mRNAs of IL-6 and IL-1alpha itself, is translationally silenced by KSRP, a protein that interacts with AU-rich elements (AREs) in these mRNAs. The second group, represented by mRNAs of IkappaBzeta and MCPIP1, is silenced independently of KSRP and AREs.Our recent observations suggest that MCPIP1 protein (auto)regulates translation of its own mRNA and that of IkappaBzeta through interaction with these mRNAs. Thus MCPIP1, recently described as an important negative feedback regulator of inflammatory gene expression, is a candidate for regulating the non-ARE group of target mRNAs by IL-1. Importantly, evidence for this kind of regulation was obtained in different cell types and also in response to bacterial lipopolysaccharide and IL-17.To elucidate the molecular mechanism of this kind of translational control, we plan to analyse MCPIP1 function in the context of the translational silencing element of IkappaBzeta mRNA. Key objectives are to obtain information on structural features of MCPIP1 required for translational silencing (including the role of its RNase activity), the interaction of MCPIP1 with other proteins, the modulation of MCPIP1 function by IL-1, and the spectrum of target mRNAs of MCPIP1.The information gained should contribute to closing a gap in our knowledge on post-transcriptional control of gene expression during inflammation.

促炎细胞因子IL-1激活转录后机制，其有助于参与免疫和炎症反应的蛋白质的表达。在第一个资助期获得的信息表明，IL-1通过抵消翻译沉默机制增加了两组不同mRNA的翻译。一组由IL-6和IL-1 α本身的mRNA代表，被KSRP沉默，KSRP是一种与这些mRNA中富含AU的元件（战神）相互作用的蛋白质。第二组是IkappaBzeta和MCPIP 1的mRNA，它们的沉默与KSRP和战神无关，我们最近的观察表明MCPIP 1蛋白（auto）通过与这些mRNA相互作用来调节自身mRNA和IkappaBzeta mRNA的翻译。因此，MCPIP 1，最近被描述为炎症基因表达的重要负反馈调节因子，是通过IL-1调节靶mRNA的非ARE组的候选者。更重要的是，这种调控在不同的细胞类型中得到了证据，也在对细菌脂多糖和IL-17的应答中得到了证据。为了阐明这种翻译调控的分子机制，我们计划在IkappaBzeta mRNA的翻译沉默元件的背景下分析MCPIP 1的功能。主要目的是获得MCPIP 1翻译沉默所需的结构特征（包括其RNase活性的作用）、MCPIP 1与其他蛋白质的相互作用、IL-1对MCPIP 1功能的调节以及MCPIP 1靶mRNA谱的信息。