School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan.
Nat Rev Mol Cell Biol. 2020 Aug;21(8):439-458. doi: 10.1038/s41580-020-0241-0. Epub 2020 May 5.
Autophagosomes are double-membrane vesicles newly formed during autophagy to engulf a wide range of intracellular material and transport this autophagic cargo to lysosomes (or vacuoles in yeasts and plants) for subsequent degradation. Autophagosome biogenesis responds to a plethora of signals and involves unique and dynamic membrane processes. Autophagy is an important cellular mechanism allowing the cell to meet various demands, and its disruption compromises homeostasis and leads to various diseases, including metabolic disorders, neurodegeneration and cancer. Thus, not surprisingly, the elucidation of the molecular mechanisms governing autophagosome biogenesis has attracted considerable interest. Key molecules and organelles involved in autophagosome biogenesis, including autophagy-related (ATG) proteins and the endoplasmic reticulum, have been discovered, and their roles and relationships have been investigated intensely. However, several fundamental questions, such as what supplies membranes/lipids to build the autophagosome and how the membrane nucleates, expands, bends into a spherical shape and finally closes, have proven difficult to address. Nonetheless, owing to recent studies with new approaches and technologies, we have begun to unveil the mechanisms underlying these processes on a molecular level. We now know that autophagosome biogenesis is a highly complex process, in which multiple proteins and lipids from various membrane sources, supported by the formation of membrane contact sites, cooperate with biophysical phenomena, including membrane shaping and liquid-liquid phase separation, to ensure seamless segregation of the autophagic cargo. Together, these studies pave the way to obtaining a holistic view of autophagosome biogenesis.
自噬体是自噬过程中形成的双层囊泡，用于吞噬广泛的细胞内物质，并将这种自噬 cargo 运输到溶酶体（或酵母和植物中的液泡）进行后续降解。自噬体生物发生响应多种信号，并涉及独特和动态的膜过程。自噬是一种重要的细胞机制，使细胞能够满足各种需求，其破坏会破坏内稳态并导致各种疾病，包括代谢紊乱、神经退行性疾病和癌症。因此，毫不奇怪，阐明控制自噬体生物发生的分子机制引起了相当大的兴趣。参与自噬体生物发生的关键分子和细胞器，包括自噬相关（ATG）蛋白和内质网，已经被发现，并且它们的作用和关系已经被深入研究。然而，一些基本问题，例如哪些膜/脂质供应来构建自噬体，以及膜如何成核、扩展、弯曲成球形并最终关闭，仍然难以解决。尽管如此，由于最近采用新方法和技术的研究，我们已经开始在分子水平上揭示这些过程的机制。我们现在知道，自噬体生物发生是一个高度复杂的过程，其中来自各种膜源的多种蛋白质和脂质，在膜接触位点形成的支持下，与包括膜成形和液-液相分离在内的生物物理现象协同作用，以确保自噬 cargo 的无缝隔离。这些研究共同为获得自噬体生物发生的整体观点铺平了道路。
