Mechanisms involved in Pexophagy

描述（由申请人提供）：自噬是一种细胞溶酶体捕获、降解和再循环细胞内容物（如胞质溶胶和细胞器）的过程，与许多疾病（如癌症、衰老、神经变性、先天免疫和程序性细胞死亡）有关。它包括几种自噬相关途径，其中选择性和非选择性地靶向货物进行溶酶体周转。选择性降解的途径包括胞质液到液泡的转运（Cvt）途径和过氧化物酶体的周转。食虫性有助于植物和人类的真菌病原体的毒力。我们的长期兴趣是了解细胞器的生物合成和营业额之间的平衡如何有助于细胞器的稳态，细胞对环境线索的反应。我们已经选择使用过氧化物酶体和酵母作为模式生物来解决这个问题。在迄今为止描述的33种自噬相关蛋白中，约有一半参与了所有自噬相关途径中的核心自噬机制，而其他蛋白则使这种核心机制适应于选择性自噬途径。我们对噬菌体特异性基因的分析揭示了超过六种噬菌体特异性的新蛋白质。我们希望从机制上阐明这些蛋白质如何适应自噬机制。此外，我们希望了解触发pexophagy的信号通路，以及过氧化物酶体生物发生和周转机制之间的串扰。该提案的具体目标是集中在以下主题：1。在食粪期间的信号事件。2.噬菌体特异蛋白的核质穿梭及其生理作用。3. Atg35在食糜中的作用和贩运4.正在进行的噬菌体特异性蛋白质的功能分析。5.在食糜期间过氧化物酶体生物合成机制的对接复合物的失活和降解。6.过氧化物酶体遗传与食糜的关系。 公共卫生相关性：我们的长期兴趣是了解细胞器合成和降解之间的平衡如何有助于亚细胞区室（如过氧化物酶体）的稳态水平。该提案旨在了解参与过氧化物酶体降解的蛋白质机制，以响应环境线索，重点关注所涉及的蛋白质和机制，以及过氧化物酶体生物发生和周转机制之间的协调。

DESCRIPTION (provided by applicant): Autophagy, a process in which the lysosomes of cells capture, degrade and recycle cellular contents, such as cytosol and organelles, has been implicated in many diseases such as cancer, ageing, neurodegeneration, innate immunity and programmed cell death. It encompasses several autophagy- related pathways in which cargos are targeted for lysosomal turnover both selectively and non-selectively. The pathways in which cargos are degraded selectively include the cytosol to vacuole transport (Cvt) pathway and peroxisome turnover by micropexophagy and macropexophagy. Pexophagy contributes to virulence in fungal pathogens of plants and humans. Our long-term interest is to understand how the balance between organelle biogenesis and turnover contribute to organelle homeostasis, a phenomenon used by cells to respond to environmental cues. We have chosen to address this problem using peroxisomes and yeast as the model organism. Of the 33 autophagy-related proteins described to date, about half are involved in the core autophagic machinery involved in all autophagy-related pathways, while the others adapt this core machinery for the selective autophagy pathways. Our analysis of pexophagy- specific genes has revealed over half a dozen new proteins that are pexophagy-specific. We wish to elucidate mechanistically how these proteins adapt the autophagy machinery. In addition, we wish to understand the signaling pathways that trigger pexophagy, as well as the cross-talk between the peroxisome biogenesis and turnover machineries. The Specific Aims of the proposal are to focus on the following topics: 1. Signaling events during pexophagy. 2. Nucleocytoplasmic shuttling of pexophagy-specific proteins and its physiological role. 3. Trafficking and role of Atg35 in pexophagy. 4. Ongoing functional analysis of pexophagy-specific proteins. 5. Inactivation and degradation of the docking complex of the peroxisome biogenesis machinery during pexophagy. 6. Connection between peroxisome inheritance and pexophagy. PUBLIC HEALTH RELEVANCE: Our long-term interest is to understand how the balance between organelle synthesis and degradation contributes to the steady-state level of subcellular compartments, such as peroxisomes. This proposal seeks to understand the protein machinery involved in peroxisome degradation in response to environmental cues, focusing on the proteins and mechanisms involved, as well as the coordination between the peroxisome biogenesis and turnover machineries.