Mechanisms involved in Pexophagy

描述（由申请人提供）：自噬是细胞溶酶体捕获、降解和回收细胞内容物（如细胞器和细胞器）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。它包括几种与自噬相关的途径，其中货物是选择性和非选择性溶酶体周转的目标。货物选择性降解的途径包括细胞质到液泡运输（Cvt）途径和过氧化物酶体通过微噬和大噬进行周转。食腐对植物和人类的真菌病原体的毒力有贡献。我们的长期兴趣是了解细胞器生物生成和更新之间的平衡如何促进细胞器稳态，这是细胞对环境信号作出反应的一种现象。我们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。在迄今所描述的33种自噬相关蛋白中，约有一半参与所有自噬相关途径中涉及的核心自噬机制，而其他蛋白则使该核心机制适应选择性自噬途径。我们对食腐特异性基因的分析揭示了超过6种新的食腐特异性蛋白质。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，我们希望了解触发自噬的信号通路，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侧重于以下主题：1。食腐过程中的信号事件。2. 噬噬特异性蛋白的核细胞质穿梭及其生理作用。3. Atg35的贩运及其在食腐中的作用。4. 正在进行的噬食特异性蛋白的功能分析。5. 食腐过程中过氧化物酶体生物发生机制对接复合体的失活和降解。6. 过氧化物酶体遗传与食腐的关系。

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.