Department of Biochemistry and Cell Biology, Max Perutz Labs, University of Vienna, Vienna BioCenter (VBC), Dr. Bohr-Gasse 9, 1030, Vienna, Austria.
Vienna BioCenter PhD Program, Doctoral School of the University of Vienna and Medical University of Vienna, Vienna, Austria.
Nat Commun. 2021 Dec 10;12(1):7194. doi: 10.1038/s41467-021-27420-3.
Autophagosomes form at the endoplasmic reticulum in mammals, and between the vacuole and the endoplasmic reticulum in yeast. However, the roles of these sites and the mechanisms regulating autophagosome formation are incompletely understood. Vac8 is required for autophagy and recruits the Atg1 kinase complex to the vacuole. Here we show that Vac8 acts as a central hub to nucleate the phagophore assembly site at the vacuolar membrane during selective autophagy. Vac8 directly recruits the cargo complex via the Atg11 scaffold. In addition, Vac8 recruits the phosphatidylinositol 3-kinase complex independently of autophagy. Cargo-dependent clustering and Vac8-dependent sequestering of these early autophagy factors, along with local Atg1 activation, promote phagophore assembly site assembly at the vacuole. Importantly, ectopic Vac8 redirects autophagosome formation to the nuclear membrane, indicating that the vacuolar membrane is not specifically required. We propose that multiple avidity-driven interactions drive the initiation and progression of selective autophagy.
自噬体在哺乳动物中在内质网上形成，在酵母中则在液泡和内质网之间形成。然而，这些部位的作用和调节自噬体形成的机制尚不完全清楚。Vac8 是自噬所必需的，它将 Atg1 激酶复合物招募到液泡上。在这里，我们表明 Vac8 作为一个中心枢纽，在选择性自噬过程中在液泡膜上引发噬菌斑组装位点。Vac8 通过 Atg11 支架直接招募货物复合物。此外，Vac8 独立于自噬招募磷酸肌醇 3-激酶复合物。货物依赖性聚集和 Vac8 依赖性隔离这些早期自噬因子，以及局部 Atg1 的激活，促进了液泡上噬菌斑组装位点的组装。重要的是，异位 Vac8 将自噬体的形成重新引导到核膜上，表明液泡膜不是特异性需要的。我们提出，多种亲和力驱动的相互作用驱动选择性自噬的起始和进展。
