Mechanisms Involved in Pexophagy

描述（由申请人提供）：所有亚细胞细胞器通过调节其数量、体积或酶含量对细胞内或细胞外信号作出反应。这种对微环境的反应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，而过氧化物酶体通过自噬机制（称为pexophagy）的降解涉及大约28个ATG和大约十几个其他基因。自噬和自噬发生在从酵母到哺乳动物的许多真核生物中。自噬作为一个领域，近年来已经爆炸，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记录了作用。在对过氧化物酶体的生物发生进行了15年的研究之后，我们已经开始对其周转进行平行的长期研究，以了解过氧化物酶体的稳态。在这个建议中解决的主要问题是（1）如何针对过氧化物酶体的micropexophagy和macropexophagy？(2)什么样的蛋白质-蛋白质相互作用和途径靶向过氧化物酶体降解？(3)Pexophagy是如何通过PI-3激酶产生PI-3-磷酸（PI-3 P）来控制的？(4)PI-3 P的产生如何允许参与pexophagy的其他蛋白质的募集和下游激活？(5)过氧化物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关于细胞器稳态如何维持的基本问题，而且还涉及关键蛋白质，如PI-3激酶和其他自噬相关蛋白质，其同系物已知在发育，细胞死亡，衰老和人类疾病中发挥重要作用。

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.