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adaptation to stress; biomacromolecule; design; human disease; insight; novel; repaired; response; single molecule; unpublished works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.

项目概要/摘要 在许多类型的人类疾病中，发病机制可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，维持它们的机制 分子/细胞水平的完整性被称为质量控制途径，它监测和修复生物体的损伤 实体。质量控制途径的干扰与多种疾病的发病机制和病理生理学有关。 人类疾病谱。有趣的是，由质量控制缺陷引起的病理特征，例如聚集 有缺陷的蛋白质和受损的细胞器经常在许多人类疾病中同时出现，这表明不同的质量控制 通路可以相互作用并组装网络以响应不同类型的细胞应激。然而，是否以及如何 它们的相互作用仍然是一个谜。我们对它们相互作用的机制的了解的模糊性极大地影响了 限制了我们对质量控制途径在发病机制中的作用的理解，以及我们同时进行的选择 减轻疾病干预中的两种病理异常。我的长期目标是了解生物学 不同的质量控制系统，它们如何合作以维持细胞/组织的完整性，以及它们的缺陷如何造成影响 对人类疾病的发病机制。目前，大多数研究都集中在单一质量控制系统的作用上，并且 人们对不同系统如何相互协作知之甚少。我之前的工作已经证明，当面对 对于线粒体应激，RQC（核糖体相关蛋白质量控制）的目标是特定蛋白的翻译停滞 由核基因组编码的一组线粒体蛋白。 RQC 生成 CTE（羧基末端延伸） 以不依赖于 40S/mRNA 模板的方式生成新生肽链。 CTE 严重修饰线粒体蛋白 损害线粒体功能，可能将 RQC 与 MQC（线粒体质量控制）联系起来。我进一步采用了新的 评估不同质量控制系统效率的方法，并开发了新的动物模型，为 分析质量控制路径之间的通信的方式。在未发表的工作中，我们发现了证据表明 来自停滞翻译机器的分裂核糖体亚基在连接不同质量水平方面具有独特且关键的作用 控制途径，并与其他细胞信号传导途径协调。在接下来的 5 年里，我的实验室将重点关注 剖析它们的分子基础。我们提出的问题是，什么信号通路连接和调节，或者可以是 在应激反应过程中，由停滞/解离的核糖体亚基连接和调节。这些问题的答案 将填补我们对基本生物学概念的知识空白，即细胞如何调动不同的质量控制 应对各种压力的途径。他们还将深入了解质量控制机制的失调如何 同时有助于疾病发病机制中同时发生的病理特征的发展。