PINK1/Parkin线粒体自噬的关键步骤是将受损线粒体隔离在称为自噬小体的双膜结构中。ATG4蛋白酶家族被认为通过处理类泛素的ATG8家族(LC3/GABARAPs)专门调节自噬小体的形成。我们发现，人类ATG4s促进自噬体形成独立于其蛋白酶活性和ATG8家族加工。ATG4邻近网络揭示了ATG4及其邻近伙伴(包括免疫疾病蛋白LRBA)在ATG9A囊泡运输到线粒体中的作用。人工智能导向的吞噬体3D电镜显示，在自噬体形成的脂质转移阶段，ATG4s促进了吞噬体与er的接触。我们还发现自噬体成熟过程中ATG8的移除并不依赖于ATG4的活性。相反，ATG4s可以分解atg8 -蛋白缀合物，揭示了ATG4s作为去泛素样酶的作用。这些发现建立了ATG4家族在ATG8脂化轴之外的非典型作用，并为快速3D电子显微镜提供了人工智能驱动的框架。
The sequestration of damaged mitochondria within double-membrane structures termed autophagosomes is a key step of PINK1/Parkin mitophagy. The ATG4 family of proteases are thought to regulate autophagosome formation exclusively by processing the ubiquitin-like ATG8 family (LC3/GABARAPs). We discover that human ATG4s promote autophagosome formation independently of their protease activity and of ATG8 family processing. ATG4 proximity networks reveal a role for ATG4s and their proximity partners, including the immune-disease protein LRBA, in ATG9A vesicle trafficking to mitochondria. Artificial intelligence-directed 3D electron microscopy of phagophores shows that ATG4s promote phagophore-ER contacts during the lipid-transfer phase of autophagosome formation. We also show that ATG8 removal during autophagosome maturation does not depend on ATG4 activity. Instead, ATG4s can disassemble ATG8-protein conjugates, revealing a role for ATG4s as deubiquitinating-like enzymes. These findings establish non-canonical roles of the ATG4 family beyond the ATG8 lipidation axis and provide an AI-driven framework for rapid 3D electron microscopy.
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