Decipher the Organization of a Multilayered Cellular Quality Control Network

项目摘要/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、大分子络合物和细胞器。在真核细胞中，维持其功能的机制 分子/细胞水平上的完整性被称为质量控制途径，它监视和修复生物损伤 实体。质量控制途径的干扰已被认为与广泛的 人类疾病的谱系。耐人寻味的是，由质量控制缺陷引起的病理特征，如聚合 有缺陷的蛋白质和受损的细胞器，经常在许多人类疾病中共存，提示不同的质量控制 在不同类型的细胞压力下，不同的通路可以相互作用并组装成一个网络。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认识存在很大的模糊性 限制了我们对质量控制途径在发病机制中的作用的理解，以及我们对同时 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，它们如何合作来维持细胞/组织的完整性，以及它们的缺陷是如何造成的 与人类疾病的发病机制有关。目前，大多数研究都集中在单一质量控制体系的作用上，并且 人们对不同系统如何相互协作知之甚少。我之前的工作证明了当我面对 对于线粒体应激，RQC(核糖体相关蛋白质量控制)的目标是特定的翻译停滞。 由核基因组编码的一组线粒体蛋白质。RQC生成CTE(羧基末端延伸) 以40S/信使核糖核酸不依赖于模板的方式合成新生的多肽链。CTE严重修饰线粒体蛋白 损害线粒体功能，潜在地将RQC与MQC(线粒体质量控制)联系在一起。我进一步采用了新的 评估不同质量控制系统效率的方法和开发的新动物模型 分析质量控制路径之间的沟通方式。在未发表的著作中，我们发现了证据 从停滞不前的翻译机器中分离出的核糖体亚基在连接不同质量水平的过程中具有独特的关键作用 控制通路，并与其他细胞信号通路协调。在接下来的5年里，我的实验室将专注于 关于解剖它们的分子基础。我们问的问题是，什么信号通路连接和调节，或者可以 在应激反应中，由停滞/解离的核糖体亚基连接和调节。这些问题的答案 将填补我们对一个基本生物学概念的认识空白，即细胞如何动员不同的质量控制 对各种压力作出反应的途径。他们还将深入了解质量控制机制的失调 同时有助于疾病发病机制中的共生病理特征的发展。

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.