Coordination of PAR and Ub signaling in mitochondria

线粒体中 PAR 和 Ub 信号传导的协调

• 批准号: 10623889
• 负责人: VALENTINA PERISSI
• 金额: $ 43.14万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623889
• 关键词: ADP ribosylation; Address; Area; Cell Death; Cell Nucleus; Communication; Complement; Dedications; Department of Defense; Disease; Enzymes; Eukaryotic Cell; Future; GPS2 gene; Gene Expression Regulation; Genetic Transcription; Genome Stability; Genomics; Homeostasis; Innate Immune Response; Link; Mediating; Metabolic; Metabolic Control; Metabolic Pathway; Mitochondria; Mitochondrial Proteins; Molecular; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of General Medical Sciences; Natural Immunity; Nuclear; Nutrient availability; Obesity; Organelles; Oxidative Stress; Pathway interactions; Physiological; Play; Positioning Attribute; Post-Translational Protein Processing; Process; Production; Regulation; Research; Role; Signal Transduction; Stress; Therapeutic; Transferase; Translational Regulation; Translations; Ubiquitin; Ubiquitination; Work; biological adaptation to stress; inhibitor; insight; malignant breast neoplasm; programs; response; targeted treatment; translational potential

Project Summary/Abstract Over the past 10 years, our research program has aimed at discovering molecular mechanisms that control metabolic adaptation in response to nutrient availability, cellular differentiation, and oxidative stress through genomic reprogramming. With NIGMS support, we have made significant contributions to identifying mechanisms responsible for the coordinated regulation of gene transcription and translation during the Mitochondrial Stress Response (MSR). Our work has identified a key role for non-degradative ubiquitination in both processes, showing that the regulated shuttling of GPS2 – an endogenous inhibitor of K63 ubiquitination – between mitochondria and nucleus is an essential strategy for maintaining mitochondrial homeostasis. As a complement to these mechanistic studies, we also investigated – in projects supported by NIDDK and the Department of Defense – the physiological relevance and translational potential GPS2-mediated regulation of ubiquitin signaling in breast cancer and obesity-associated disorders. Together, these studies have revealed the importance of GPS2-mediated restriction of K63Ub signaling in promoting metabolic adaptation and mitochondria remodeling during stress and cellular differentiation. This large body of work highlights our expertise in the field and our unique position to further investigate the crosstalk between this newly identified pathway and other PTMs involved in regulating mitochondrial function. In particular, we will focus our future studies on the crosstalk between ubiquitination and ADP-ribosylation. These PTMs work in tandem in the regulation of nuclear genome stability, innate immunity and stress-induced translational regulation. However, their relationship in regulating mitochondrial function has not yet been investigated. In fact, although the presence of ADP-ribosylation activity in mitochondria was known for decades, the identity of the mitochondrial ART enzyme/s has been elusive, hindering more detailed studies on the role and regulation of mitochondrial proteins through ADP-ribosylation. As we recently identified NEURL4 as a mitochondria-dedicated ADP-ribosyl transferase under the regulation of stress-induced and GPS2-mediated reprogramming, we are now in the position of carrying those studies. We propose a research plan spanning two major areas:1) Investigating the spatial and functional regulation of mitochondria retrograde signaling in response to mitochondrial stress and 2) Exploring the crosstalk between ubiquitination and ADP-ribosylation in regulating mitochondrial homeostasis. Our research plan addresses three key problems: i) the spatial regulation of mitochondria retrograde signaling; ii) the functional contribution of mitochondria retrograde signaling to the regulation of ADP-ribosylation and ubiquitination across subcellular compartments; iii) the molecular mechanisms underlying the coordinated regulation of ADP-ribosylation/ ubiquitination. Successful completion of the proposed studies will lead to a better understanding of the mechanisms regulating mitochondria homeostasis through post-translational modifications and possibly reveal regulatory strategies to be targeted for therapeutic purposes.

项目概要/摘要 在过去的 10 年里，我们的研究项目旨在发现控制的分子机制 通过代谢适应来响应营养可用性、细胞分化和氧化应激 基因组重编程。在 NIGMS 的支持下，我们为识别 负责协调调控基因转录和翻译的机制 线粒体应激反应（MSR）。我们的工作确定了非降解泛素化在 这两个过程都表明 GPS2（K63 泛素化的内源性抑制剂）的调节穿梭 线粒体和细胞核之间的相互作用是维持线粒体稳态的重要策略。作为一个 作为这些机制研究的补充，我们还在 NIDDK 和 国防部 – GPS2 介导的生理相关性和翻译潜力调节 乳腺癌和肥胖相关疾病中的泛素信号传导。这些研究共同揭示了 GPS2 介导的 K63Ub 信号传导限制在促进代谢适应中的重要性 应激和细胞分化过程中线粒体重塑。这一庞大的作品凸显了我们的 该领域的专业知识以及我们在进一步调查这一新发现之间的串扰方面的独特地位 途径和其他参与调节线粒体功能的 PTM。我们将特别关注我们的未来 泛素化和ADP-核糖基化之间的串扰研究。这些 PTM 协同工作 核基因组稳定性、先天免疫和应激诱导的翻译调节的调节。然而， 它们在调节线粒体功能中的关系尚未得到研究。事实上，虽然存在 线粒体中 ADP-核糖基化活性的已知数十年，线粒体 ART 的身份 酶一直难以捉摸，阻碍了对线粒体蛋白的作用和调节进行更详细的研究 通过ADP-核糖基化。正如我们最近确定 NEURL4 是线粒体专用的 ADP-核糖基 在应激诱导和 GPS2 介导的重编程的调节下，我们现在正处于 进行这些研究的位置。我们提出了一个涵盖两个主要领域的研究计划：1）调查 线粒体逆行信号传导响应线粒体应激的空间和功能调节；2) 探索泛素化和 ADP-核糖基化在调节线粒体稳态中的串扰。 我们的研究计划解决三个关键问题：i）线粒体逆行信号的空间调控； ii) 线粒体逆行信号对 ADP-核糖基化调节的功能贡献和 跨亚细胞区室的泛素化； iii) 协调的分子机制 ADP-核糖基化/泛素化的调节。成功完成拟议的研究将带来更好的结果 了解通过翻译后修饰调节线粒体稳态的机制 并可能揭示针对治疗目的的监管策略。