Mechanisms of non-centrosomal microtubule-organizing center functions

非中心体微管组织中心功能的机制

• 批准号: 10360430
• 负责人: TIMOTHY L MEGRAW
• 金额: $ 30.36万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10360430
• 关键词: Animals; Architecture; Basement membrane; Binding; Biochemistry; Biological Assay; Cell Differentiation process; Cell physiology; Cells; Cellular biology; Centrosome; Collagen; Complex; Development; Disease; Dynein ATPase; Etiology; Fat Body; Generations; Goals; Homeostasis; Knowledge; Liver; Location; Maps; Measures; Membrane Proteins; Microtubule-Organizing Center; Microtubules; Modeling; Molecular; Molecular Structure; Motor; Nature; Nuclear; Organ; Orthologous Gene; Outcome; Physiological; Physiology; Polymerase; Positioning Attribute; Process; Protein Isoforms; Proteins; Radial; Regulation; Role; Structure; Surface; Testing; Vesicle; Work; cell type; frontier; gamma Tubulin; human disease; infancy; ninein; novel; protein complex; recruit; synergism; trafficking

Centrosomes are the major and best-understood microtubule-organizing centers (MTOCs) in animal cells, yet in most differentiated cells non-centrosomal MTOCs (ncMTOCs) redirect MT organization instead of the centrosome. The sheer diversity of ncMTOCs reflects the different functions of various cell types and the subcellular locations and mechanisms of MT assembly that serve those roles. Understanding the molecular architecture of these ncMTOCs, the mechanisms of MT assembly they employ, and the functions they serve to the diverse cell types they serve remains an important frontier in cell biology and disease. The few ncMTOCs that have been deciphered reveal architectures and mechanisms of MT assembly as diverse as the functions they serve for the varied cell types. In this proposal we expand on a project to define the functions of a perinuclear ncMTOC in fat body cells which serves the cell by providing nuclear positioning and is essential for retrograde endosomal trafficking to support the vital secretory roles of this cell type. We will determine the unique molecular mechanisms of MT assembly by two distinct protein complexes that control MT assembly/nucleation from this ncMTOC. Specifically, this proposal aims to further define the structure of the fat body ncMTOC on the nuclear surface, and to define the mechanisms of MT assembly by Patronin and Ninein and how they cooperate with the microtubule polymerase Minispindles (Msps) and other partners to nucleate MTs. The outcomes of this project will be a definitive and novel understanding of the molecular and physiological functions of the fat body ncMTOC, revealing potentially novel disease etiologies for the proteins involved and the processes that they regulate. Moreover, as a molecular MT nucleation paradigm that is independent of the widespread microtubule nucleator gamma-tubulin, we will define at least one new mechanism to generate MTs at MTOCs.

中心体是主要且最了解的微管组织中心 （MTOC）存在于动物细胞中，但在大多数分化细胞中是非中心体 MTOC (ncMTOCs) 重定向 MT 组织而不是中心体。纯粹的 ncMTOC的多样性反映了不同细胞类型的不同功能和 发挥这些作用的 MT 组装的亚细胞位置和机制。 了解这些 ncMTOC 的分子结构、机制 他们使用的 MT 组装，以及他们为不同细胞类型提供的功能 它们仍然是细胞生物学和疾病的重要前沿领域。少数人 已破译的 ncMTOC 揭示了 MT 组装的多样性与它们为不同细胞类型提供的功能一样多样。在 这个提案我们扩展了一个项目来定义核周的功能 脂肪体细胞中的 ncMTOC 通过提供核定位为细胞服务 对于逆行内体运输以支持重要的分泌至关重要 这种细胞类型的作用。我们将确定MT独特的分子机制 由控制 MT 组装/成核的两种不同蛋白质复合物组装 来自这个 ncMTOC。具体来说，该提案旨在进一步定义结构 核表面的脂肪体 ncMTOC，并定义其机制 Patronin 和 Ninein 的 MT 组装以及他们如何与 微管聚合酶 Minispindles (Msps) 和其他伙伴使 MT 成核。 该项目的成果将是对 脂肪体 ncMTOC 的分子和生理功能，揭示 所涉及的蛋白质和过程的潜在新疾病病因 他们监管。此外，作为分子 MT 成核范式， 独立于广泛存在的微管成核剂γ-微管蛋白，我们将 定义至少一种在 MTOC 生成 MT 的新机制。