Mechanisms involved in Pexophagy

描述(申请人提供)：自噬，细胞的溶酶体捕获、降解和回收细胞内容物，如胞浆和细胞器的过程，与许多疾病有关，如癌症、衰老、神经退化、先天免疫和细胞程序性死亡。它包括几个与自噬相关的途径，在这些途径中，货物选择性地和非选择性地以溶酶体周转为靶标。货物选择性降解的途径包括胞浆到空泡的运输(CVT)途径、通过小噬菌体和大噬菌体的过氧化物体周转。在植物和人类的真菌病原体中，嗜食性是致病因素之一。我们的长期兴趣是了解细胞器生物发生和周转之间的平衡如何有助于细胞器的动态平衡，这是细胞用来对环境提示做出反应的一种现象。我们选择使用过氧化酶体和酵母作为模式生物来解决这个问题。在迄今描述的33个自噬相关蛋白中，约有一半参与了所有自噬相关途径所涉及的核心自噬机制，而其他蛋白则为选择性自噬途径调整了这一核心机制。我们对食欲特异基因的分析揭示了超过六种新的食欲特异蛋白质。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，我们希望了解触发吞噬作用的信号通路，以及过氧化体生物发生和周转机制之间的相互作用。该提案的具体目的是集中在以下主题上：1.食欲不振期间的信号事件。2.噬菌体特异蛋白的核质穿梭及其生理作用。3.Atg35的贩运及其在食欲病中的作用。4.正在进行的食欲菌特异蛋白的功能分析。5.吞噬过程中过氧化体生物发生机制对接复合体的失活和降解。6.过氧化体遗传与食腐病的关系。 与公共健康相关：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室的稳定水平，如过氧化物体。这一建议试图了解参与过氧化物体降解的蛋白质机制对环境线索的响应，重点是所涉及的蛋白质和机制，以及过氧化物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.