Mechanisms Involved in Pexophagy

Pexophagy 涉及的机制

• 批准号: 7269482
• 负责人: Suresh Subramani
• 金额: $ 26.45万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7269482
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Aging; Antithymoglobulin; Autophagocytosis; Binding; Biogenesis; Cell Aging; Cell Death; Cells; Complex; Coupled; Cues; Development; Equilibrium; Eukaryota; Eukaryotic Cell; Event; Genes; Homeostasis; Homologous Gene; Link; Longitudinal Studies; Mammals; Mediating; Membrane Fusion; Modeling; Molecular; Natural Immunity; Neurodegenerative Disorders; Numbers; Organelles; Pathway interactions; Phosphate-Binding Proteins; Phosphotransferases; Pichia; Play; Process; Production; Proteins; Recruitment Activity; Repression; Role; Tertiary Protein Structure; Testing; Time; Ubiquitin Like Proteins; Vacuole; Work; Yeasts; base; cancer cell; extracellular; human disease; inorganic phosphate; interest; intracellular protein transport; member; mutant; pathogen; peroxisome; protein function; protein localization location; protein protein interaction; scaffold; segregation

DESCRIPTION (provided by applicant): All subcellular organelles respond to intracellular or extracellular cues by modulation of their number, volume or enzymatic content. This ability to respond to their microenvironment allows cells to maintain organelle homeostasis, which is determined at steady-state by the balance between biogenesis and degradation. Peroxisome biogenesis, division and segregation require about 32 PEX genes, while peroxisome degradation by autophagic mechanisms (termed pexophagy) involves about 28 ATG, and about a dozen other, genes. Autophagy and pexophagy occur in many eukaryotes from yeast to mammals. Autophagy, as a field, has exploded in recent years with roles documented in cellular aging, cancer, cell development, neurodegenerative diseases, cell death, and in innate immunity against pathogens. After 15 years of work on the biogenesis of peroxisomes, we have embarked on parallel long- term studies of their turnover, to understand peroxisome homeostasis. The major questions addressed in this proposal are (1) How are peroxisomes targeted for micropexophagy and macropexophagy? (2) What protein-protein interactions and pathways target peroxisomes for degradation? (3) How is pexophagy controlled by production of PI-3-phosphate (PI-3P) by PI-3 kinase? (4) How does the production of PI-3P allow the recruitment and the downstream activation of other proteins involved in pexophagy? (5) How are the peroxisome biogenesis and turnover machineries coupled? This work not only addresses fundamental questions regarding how organelle homeostasis is maintained, but also deals with key proteins such as PI-3 Kinases and other autophagy-related proteins whose homologues are known to play important roles in development, cell death, aging and human diseases.

描述(申请人提供)：所有亚细胞细胞器通过调节它们的数量、体积或酶含量来对细胞内或细胞外的提示做出反应。这种对微环境做出反应的能力使细胞能够维持细胞器的稳态，这是由生物发生和降解之间的平衡决定的。过氧化物酶体的生物发生、分裂和分离需要大约32个PEX基因，而通过自噬机制(称为吞噬作用)的过氧化物体降解涉及大约28个ATG和大约12个其他基因。从酵母到哺乳动物，许多真核生物中都存在自噬和正吞噬现象。近年来，自噬作为一个领域，在细胞衰老、癌症、细胞发育、神经退行性疾病、细胞死亡和对病原体的先天免疫中的作用被证明是爆炸性的。经过15年对过氧化酶体生物发生的研究，我们开始了对其周转的平行的长期研究，以了解过氧化酶体的动态平衡。这项提案中涉及的主要问题是：(1)如何将过氧化体定位于微噬菌体和巨噬菌体？(2)什么蛋白质-蛋白质相互作用和途径针对过氧化物体进行降解？(3)由PI-3激酶产生PI-3-磷酸(PI-3P)是如何控制吞噬作用的？(4)PI-3P的产生如何允许与吞噬相关的其他蛋白质的招募和下游激活？(5)过氧酶体的生物发生和周转机制是如何耦合的？这项工作不仅解决了细胞器如何维持动态平衡的基本问题，而且还涉及关键蛋白，如PI-3激酶和其他自噬相关蛋白，它们的同源蛋白在发育、细胞死亡、衰老和人类疾病中发挥着重要作用。