Decipher the Organization of a Multilayered Cellular Quality Control Network

破译多层细胞质量控制网络的组织

• 批准号: 10660129
• 负责人: Zhihao Wu
• 金额: $ 36.19万
• 依托单位: SOUTHERN METHODIST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660129
• 关键词: Adopted; Animal Model; Biological; Biology; Cells; Cellular Stress; Communication; Complex; Defect; Development; Disease; Dissociation; Eukaryotic Cell; Functional disorder; Genome; Goals; Impairment; Intervention; Knowledge; Link; Macromolecular Complexes; Messenger RNA; Methodology; Mitochondria; Mitochondrial Proteins; Molecular; Monitor; Nuclear; Organelles; Pathogenesis; Pathologic; Pathway interactions; Peptides; Proteins; Quality Control; Research; Ribosomes; Role; Signal Pathway; Stress; Structure; System; Tissues; Translations; Work; biological adaptation to stress; biomacromolecule; design; human disease; insight; novel; repaired; response; single molecule; unpublished works

PROJECT SUMMARY/ABSTRACT In many types of human diseases, pathogenesis can be attributed to impaired structure or function of biomacromolecules, including biomolecules, macromolecular complexes, and organelles. In eukaryotic cells, mechanisms of maintaining their integrity at the molecular/cellular level is known as quality control pathways, which monitor and repair damage to biological entities. Interference of the quality control pathways has been linked to the pathogenesis and pathophysiology of a wide spectrum of human diseases. Intriguingly, pathological hallmarks caused by quality control defects, such as aggregation of defective proteins and damaged organelles, often co-occur in many human diseases, suggesting that different quality control pathways may interact and assemble a network in response to diverse type of cellular stress. However, whether and how they interact remains a mystery. The ambiguity in our knowledge of the mechanisms by which they interact has significantly limited our understanding of the role of quality control pathways in pathogenesis, as well as our options for simultaneously mitigating both pathological abnormalities in disease interventions. My long-term goal is to understand the biology of different quality control systems, how they cooperate to maintain cell/tissue integrity, and how their deficiencies contribute to the pathogenesis of human diseases. Currently, most research focuses on the role of a single quality control system, and little is known about how different systems cooperate with each other. My previous work has demonstrated that when faced with mitochondrial stress, RQC (ribosome-associated protein quality control) targets the translational arrest of a specific group of mitochondrial proteins encoded by the nuclear genome. RQC generates CTEs (carboxyl-terminus extensions) on nascent peptide chains in a 40S/mRNA template-independent manner. CTE-modified mitochondrial proteins severely impair mitochondrial function, potentially linking RQC to MQC (mitochondrial quality control). I have further adopted new methodologies to assess the efficiency of different quality control systems and developed novel animal models that pave the way for analyzing the communication between quality control pathways. In unpublished work, we found evidence that split ribosomal subunits from stalled translation machinery have unique and critical roles in linking different levels of quality controls pathways, and in coordination with other cellular signaling pathways. For the next 5-year period, my lab will focus on dissecting their molecular basis. The questions we ask are, what signaling pathways connect and regulate, or can be connected and regulated by stalled/dissociated ribosomal subunits, during stress response. The answer to these questions will fill gaps in our knowledge of a fundamental biological concept, namely how cells mobilize different quality control pathways in response to various stresses. They will also gain insights into how dysregulation of quality control mechanisms simultaneously contributes to the development of co-occurring pathological features in disease pathogenesis.

项目摘要/摘要 在许多类型的人类疾病中，发病机理可以归因于生物大分子的结构或功能受损， 包括生物分子，大分子复合物和细胞器。在真核细胞中，维持其的机制 分子/细胞水平的完整性称为质量控制途径，该途径监测和修复生物学的损害 实体。质量控制途径的干扰已与广泛的发病机理和病理生理有关 人类疾病的范围。有趣的是，由质量控制缺陷引起的病理标志，例如聚集 有缺陷的蛋白质和受损细胞器，通常在许多人类疾病中同时发生，表明不同的质量控制 途径可能会响应各种类型的细胞应激而相互作用并组装网络。但是，是否以及如何 他们互动仍然是一个谜。我们对它们相互作用的机制的了解的模棱两可 限制我们对质量控制途径在发病机理中的作用的理解，以及同时选择的选择 减轻疾病干预中的两种病理异常。我的长期目标是了解 不同的质量控制系统，如何合作维持细胞/组织完整性以及它们的缺陷如何贡献 人类疾病的发病机理。目前，大多数研究都集中在单个质量控制系统的作用上，以及 关于不同的系统如何相互配合的知之甚少。我以前的工作已经表明，面对 RQC（核糖体相关蛋白质质量控​​制）以线粒体应力为目标。 由核基因组编码的线粒体蛋白组。 RQC生成CTE（羧基末端扩展） 新生肽链以40s/mRNA模板独立的方式。 CTE修饰的线粒体蛋白严重 损害线粒体功能，可能将RQC与MQC联系起来（线粒体质量控制）。我进一步采用了新的 评估不同质量控制系统效率和开发新型动物模型的方法论 分析质量控制途径之间的通信的方式。在未发表的工作中，我们发现证据表明 分割的核糖体亚基从停滞的翻译机械中具有独特的和关键的作用在链接不同级别的质量 控制途径，并与其他细胞信号通路协调。在接下来的5年期间，我的实验室将集中精力 解剖其分子基础。我们问的问题是，什么信号通路连接和调节，或者可以是 在应力反应期间，由失速/解离的核糖体亚基连接并调节。这些问题的答案 将在我们对基本生物学概念的知识中填补空白，即细胞如何动员不同的质量控制 响应各种应力的途径。他们还将深入了解质量控制机制的失调 同时有助于发展疾病发病机理中同时发生的病理特征。