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Function and regulation of ARTD10-dependent mono-ADP-ribosylation in signaling and gene transcription

ARTD10 依赖性单 ADP 核糖基化在信号传导和基因转录中的功能和调节

基本信息

批准号：
246008064
负责人：
Professor Dr. Bernhard Lüscher
金额：
--
依托单位：
Institut für Biochemie und Molekularbiologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2013
资助国家：
德国
起止时间：
2012-12-31 至 2021-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/246008064?language=en
关键词：
Function regulation ARTD10 dependent mono

项目摘要

Posttranslational modifications (PTMs) of proteins play a key role in the propagation of information in cells. PTMs control the functionality of proteins by altering their properties, including stability, subcellular localization, interaction with other macromolecules, and enzymatic activity. Among the many different known PTMs, ADP-ribosylation is rapidly emerging as a modification that controls central pathways in cells, which are associated with for example inflammation, cancer and neurodegeneration. ADP-ribosylation involves enzymes that transfer ADP-ribose (ADPr) from the cofactor NAD+ onto substrates. We have identified with ARTD10 the first intracellular, resident mono-ADP-ribosyltransferase of mammalian cells and our recent studies provide initial evidence relevant to understand basic features of mono-ADP-ribosylation (MARylation). Our findings suggest that (i) MARylation occurs in cells and controls physiological processes, (ii) is a reversible PTM as we have identified specific macrodomains that hydrolyze the ester bond between the ADPr and the glutamate side chain, (iii) is read by specific protein domains, i.e. macrodomains of ARTD8, and (iv) controls multiple signaling pathways inferred from the identified substrates. While these initial findings provide a framework of basic knowledge, many questions arise that need to be addressed to more fully understand the regulatory potential and the biology of MARylation and the enzymes involved in writing, reading and erasing this PTM. In this proposal we will concentrate on the analysis of specific key questions, whose answers will allow us to further expand our knowledge of the role of MARylation and the enzymes associated with this PTM in the control of specific proteins and pathways and of gene expression. At the center is the interaction of ARTD10-dependent mono-ADP-ribosylated substrates with the macrodomains of ARTD8. We will use and further develop these macrodomains as tools to define MARylation. We will modulate ARTD10 activity, either by overexpression, by knockdown, or by regulating the activity of MAR hydrolases to control MARylation. The mapping of MARylation sites will allow us to further develop the mechanistic aspects of this PTM as a regulator of enzymes such as kinases. Moreover we will evaluate the relevance of the interaction of ARTD8 with ARTD10. Finally we will address the role of ARTD10 and ARTD8 and MARylation in the organization of chromatin and in the regulation of gene transcription to define how this PTM affects the use of genomic information also considering the interplay with other histone marks. With these studies, all based on our own work, we will contribute considerably to our understanding of MARylation and its role in controlling key physiological processes.

蛋白质的翻译后修饰（PTMs）在细胞中的信息传播中起着关键作用。PTMs通过改变蛋白质的性质（包括稳定性、亚细胞定位、与其他大分子的相互作用和酶活性）来控制蛋白质的功能。在许多不同的已知PTMs中，adp核糖基化作为一种控制细胞中枢通路的修饰正在迅速出现，这些通路与炎症、癌症和神经变性等有关。adp核糖基化涉及将adp核糖（ADPr）从辅因子NAD+转移到底物上的酶。我们已经用ARTD10确定了哺乳动物细胞内第一个驻留的单adp核糖基转移酶，我们最近的研究为理解单adp核糖基化（MARylation）的基本特征提供了初步证据。我们的研究结果表明：(i) MARylation发生在细胞中并控制生理过程，（ii）是一个可逆的PTM，因为我们已经确定了水解ADPr和谷氨酸侧链之间的酯键的特定大结构域，（iii）被特定的蛋白质结构域读取，即ARTD8的大结构域，以及（iv）控制从鉴定的底物推断的多种信号通路。虽然这些初步发现提供了一个基本知识框架，但为了更充分地了解MARylation的调控潜力和生物学，以及参与编写、读取和删除PTM的酶，还需要解决许多问题。在本提案中，我们将集中分析特定的关键问题，这些问题的答案将使我们进一步扩展我们对MARylation和与该PTM相关的酶在控制特定蛋白质和途径以及基因表达中的作用的认识。中心是artd10依赖的单adp核糖基化底物与ARTD8的大结构域的相互作用。我们将使用并进一步开发这些宏域作为定义MARylation的工具。我们将通过过表达、敲低或调节MAR水解酶的活性来控制MARylation来调节ARTD10的活性。MARylation位点的定位将使我们能够进一步开发PTM作为酶（如激酶）调节剂的机制。此外，我们将评估ARTD8与ARTD10相互作用的相关性。最后，我们将讨论ARTD10和ARTD8以及MARylation在染色质组织和基因转录调控中的作用，以确定PTM如何影响基因组信息的使用，同时考虑到与其他组蛋白标记的相互作用。这些研究都是基于我们自己的工作，我们将大大有助于我们对MARylation及其在控制关键生理过程中的作用的理解。