Mechanisms of Autophagy

自噬机制

• 批准号: 10265219
• 负责人: Richard James Youle
• 金额: $ 60.23万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10265219
• 关键词: AGFG1 gene; Autophagocytosis; Autophagosome; Binding; Biogenesis; Cells; Encapsulated; Eukaryotic Cell; Family member; GTPase-Activating Proteins; Generations; Lysosomes; Maintenance; Mammals; Mediating; Membrane; Mitochondria; Molecular; Morphogenesis; Morphology; Mus; Mutate; Nerve Degeneration; Neurons; Nutrient; Organelles; PINK1 gene; Parkinson Disease; Pathway interactions; Play; Proteins; Quality Control; Role; Starvation; Time; Ubiquitin; extracellular; gene product; misfolded protein; parkin gene/protein; protein aggregation; rab GTP-Binding Proteins; recruit

Autophagy is known to be required for eukaryotic cells to withstand nutrient starvation by mediating the degradation of cellular components to supply substrates for ATP generation thereby helping cells survive until extracellular nutrient availability returns. Autophagy also mediates forms of quality control within cells by engulfing and degrading protein aggregates and damaged mitochondria that mitigates neurodegeneration in mice. Autophagy substrates become encapsulated by a double membrane structure that then fuses with lysosomes to mediate degradation of the cargo. How autophagosomes form and how their substrates are recognized for engulfment remain poorly understood. Although two gene products mutated in Parkinson's disease, PINK1, and Parkin have been found to play a central role in triggering mitophagy in mammals, how the pre-autophagosomal isolation membrane selectively and accurately engulfs damaged mitochondria remains unclear. RABGEF1, an upstream factor of the endosomal Rab GTPase cascade, is recruited to damaged mitochondria via ubiquitin binding downstream of Parkin. RABGEF1 directs the downstream Rab proteins, RAB5 and RAB7A, to damaged mitochondria, whose associations are further regulated by mitochondrial Rab-GAPs. TBC1D15, a mitochondrial Rab GTPase-activating protein (Rab-GAP), governs autophagosome biogenesis and morphology. To constrain autophagosome morphogenesis to that of the cargo, TBC1D15 inhibits Rab7 activity and associates with both the mitochondria through binding Fis1 and the isolation membrane through the interactions with LC3/GABARAP family members. Another TBC family member TBC1D17, also participates in mitophagy and forms homodimers and heterodimers with TBC1D15. These results demonstrate that TBC1D15 and TBC1D17 mediate proper autophagic encapsulation of mitochondria by regulating Rab7 activity at the interface between mitochondria and isolation membranes and that endosomal Rab cycles on damaged mitochondria are crucial regulators of mitophagy.

已知真核细胞需要自噬来抵抗营养饥饿，通过介导细胞成分的降解来提供 ATP 生成的底物，从而帮助细胞生存，直到细胞外营养可用性恢复。自噬还通过吞噬和降解蛋白质聚集体和受损的线粒体来介导细胞内的质量控制，从而减轻小鼠的神经退行性变。 自噬底物被双层膜结构封装，然后与溶酶体融合以介导货物的降解。 自噬体是如何形成的以及它们的底物如何被识别并吞噬仍然知之甚少。 尽管帕金森病中的两个基因产物PINK1和Parkin已被发现在触发哺乳动物线粒体自噬中发挥核心作用，但自噬体前隔离膜如何选择性且准确地吞噬受损的线粒体仍不清楚。 RABGEF1 是内体 Rab GTP 酶级联的上游因子，通过 Parkin 下游的泛素结合被招募到受损的线粒体。 RABGEF1 将下游 Rab 蛋白 RAB5 和 RAB7A 引导至受损的线粒体，其关联进一步受到线粒体 Rab-GAP 的调节。 TBC1D15 是一种线粒体 Rab GTP 酶激活蛋白 (Rab-GAP)，控制自噬体的生物发生和形态。为了将自噬体形态发生限制为货物的形态发生，TBC1D15 抑制 Rab7 活性，并通过结合 Fis1 与线粒体结合，并通过与 LC3/GABARAP 家族成员的相互作用与隔离膜结合。另一个TBC家族成员TBC1D17也参与线粒体自噬并与TBC1D15形成同二聚体和异二聚体。这些结果表明，TBC1D15 和 TBC1D17 通过调节线粒体和隔离膜之间界面的 Rab7 活性来介导线粒体的适当自噬封装，并且受损线粒体上的内体 Rab 循环是线粒体自噬的关键调节因子。