Broadbent D G, McEwan C M, Tsang T M, Poole D M, Naylor B C, Price J C, Schmidt J C, Andersen J L
Institute for Quantitative Health Sciences and Engineering, Michigan State University, East Lansing, MI, USA.
College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA.
bioRxiv. 2023 Nov 29:2023.11.28.569058. doi: 10.1101/2023.11.28.569058.
Autophagy is an essential cellular recycling process that maintains protein and organelle homeostasis. ATG9A vesicle recruitment is a critical early step in autophagy to initiate autophagosome biogenesis. The mechanisms of ATG9A vesicle recruitment are best understood in the context of starvation-induced non-selective autophagy, whereas less is known about the signals driving ATG9A vesicle recruitment to autophagy initiation sites in the absence of nutrient stress. Here we demonstrate that loss of ATG9A or the lipid transfer protein ATG2 leads to the accumulation of phosphorylated p62 aggregates in the context of basal autophagy. Furthermore, we show that p62 degradation requires the lipid scramblase activity of ATG9A. Lastly, we present evidence that poly-ubiquitin is an essential signal that recruits ATG9A and mediates autophagy foci assembly in nutrient replete cells. Together, our data support a ubiquitin-driven model of ATG9A recruitment and autophagosome formation during basal autophagy.
自噬是一种维持蛋白质和细胞器稳态的重要细胞循环过程。ATG9A囊泡募集是自噬中启动自噬体生物发生的关键早期步骤。在饥饿诱导的非选择性自噬背景下，对ATG9A囊泡募集机制的理解最为深入，而在缺乏营养应激的情况下，驱动ATG9A囊泡募集到自噬起始位点的信号则知之甚少。在这里，我们证明在基础自噬情况下，ATG9A或脂质转运蛋白ATG2的缺失会导致磷酸化p62聚集体的积累。此外，我们表明p62降解需要ATG9A的脂质翻转酶活性。最后，我们提供证据表明多聚泛素是一种重要信号，可募集ATG9A并介导营养充足细胞中的自噬焦点组装。总之，我们的数据支持基础自噬过程中泛素驱动的ATG9A募集和自噬体形成模型。
