The biogenesis of mammalian autophagosomes remains to be fully defined. Here, we used cellular and in vitro membrane fusion analyses to show that autophagosomes are formed from a hitherto unappreciated hybrid membrane compartment. The autophagic precursors emerge through fusion of FIP200 vesicles, derived from the cis-Golgi, with endosomally derived ATG16L1 membranes to generate a hybrid pre-autophagosomal structure, HyPAS. A previously unrecognized apparatus defined here controls HyPAS biogenesis and mammalian autophagosomal precursor membranes. HyPAS can be modulated by pharmacological agents whereas its formation is inhibited upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or by expression of SARS-CoV-2 nsp6. These findings reveal the origin of mammalian autophagosomal membranes, which emerge via convergence of secretory and endosomal pathways, and show that this process is targeted by microbial factors such as coronaviral membrane-modulating proteins.

哺乳动物自噬体的生物发生仍有待完全确定。在这里，我们使用细胞和体外膜融合分析来表明自噬体是由迄今为止未被认可的混合膜室形成的。自噬前体是通过源自顺式高尔基体的 FIP200 囊泡与内体衍生的 ATG16L1 膜融合而产生的，从而产生混合的自噬体前结构 HyPAS。这里定义的一个以前未被认识的装置控制着 HyPAS 生物发生和哺乳动物自噬体前体膜。HyPAS 可以通过药物调节，而其形成在严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 感染或 SARS-CoV-2 nsp6 表达时受到抑制。这些发现揭示了哺乳动物自噬体膜的起源，该膜是通过分泌和内体途径的汇聚而出现的，并表明该过程是冠状病毒膜调节蛋白等微生物因子的靶标。