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.

项目摘要/摘要 在过去的10年中，我们的研究计划旨在发现控制分子机制 响应养分可用性，细胞分化和氧化应激的代谢适应 基因组重编程。在纽格斯的支持下，我们为确定 负责协调基因转录和翻译调节的机制 线粒体应力反应（MSR）。我们的工作已经确定了非降解性泛素化的关键作用 这两个过程均表明GPS2的班车 - 一种K63泛素化的内源性抑制剂 - 线粒体和核之间是维持线粒体稳态的重要策略。作为 我们还对这些机械研究的补充进行了研究 - 在NIDDK和NIDDK支持的项目中 国防部 - 物理相关性和转化的潜在GPS2介导的法规 乳腺癌和肥胖相关疾病中的泛素信号传导。这些研究一起揭示了 GPS2介导的K63UB信号传导限制在促进代谢适应和 线粒体在应力和细胞分化过程中进行重塑。这么大的作品突出了我们的 该领域的专业知识以及我们的独特立场，以进一步研究这一新确定的串扰 涉及调节线粒体功能的途径和其他PTM。特别是，我们将集中精力 关于泛素化和ADP-核糖基化之间的串扰的研究。这些PTM在 核基因组稳定性，先天免疫学和压力引起的翻译调节的调节。然而， 它们在调节线粒体功能方面的关系尚未得到研究。实际上，尽管存在 线粒体中的ADP-核糖基化活性数十年来，线粒体的身份 酶/s一直难以捉摸，阻碍了有关线粒体蛋白的作用和调节的更详细的研究 通过ADP-核糖基化。正如我们最近确定的Neurl4是线粒体划定的ADP-核糖基 在压力诱导和GPS2介导的重编程的调节下转移酶，我们现在在 携带这些研究的位置。我们提出了一个跨越两个主要领域的研究计划：1）调查 线粒体应激响应线粒体逆行信号的空间和功能调节，2） 在调节线粒体稳态时探索泛素化和ADP-核糖基化之间的串扰。 我们的研究计划解决了三个关键问题：i）线粒体逆行信号的空间调节； ii）线粒体逆行信号传导对ADP-核糖基化和调节的功能贡献 跨细胞室的泛素化； iii）协调的分子机制 调节ADP-核糖基化/泛素化。成功完成拟议的研究将导致更好 了解通过翻译后修饰来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。