Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
Department of Genetics, Graduate School of Medicine, Osaka University, Osaka, Japan.
Nat Commun. 2024 Aug 21;15(1):7194. doi: 10.1038/s41467-024-51402-w.
Autophagy is a highly conserved process from yeast to mammals in which intracellular materials are engulfed by a double-membrane organelle called autophagosome and degrading materials by fusing with the lysosome. The process of autophagy is regulated by sequential recruitment and function of autophagy-related (Atg) proteins. Genetic hierarchical analyses show that the ULK1 complex comprised of ULK1-FIP200-ATG13-ATG101 translocating from the cytosol to autophagosome formation sites as a most upstream ATG factor; this translocation is critical in autophagy initiation. However, how this translocation occurs remains unclear. Here, we show that ULK1 is palmitoylated by palmitoyltransferase ZDHHC13 and translocated to the autophagosome formation site upon autophagy induction. We find that the ULK1 palmitoylation is required for autophagy initiation. Moreover, the ULK1 palmitoylated enhances the phosphorylation of ATG14L, which is required for activating PI3-Kinase and producing phosphatidylinositol 3-phosphate, one of the autophagosome membrane's lipids. Our results reveal how the most upstream ULK1 complex translocates to the autophagosome formation sites during autophagy.
自噬是一个从酵母到哺乳动物高度保守的过程，在这个过程中，细胞内物质被称为自噬体的双层膜细胞器包裹，并通过与溶酶体融合来降解物质。自噬的过程受自噬相关（Atg）蛋白的顺序募集和功能调节。遗传层次分析表明，由 ULK1-FIP200-ATG13-ATG101 组成的 ULK1 复合物从细胞质转移到自噬体形成部位作为最上游的 ATG 因子；这种易位对于自噬的起始至关重要。然而，这种易位是如何发生的仍不清楚。在这里，我们发现 ULK1 被棕榈酰转移酶 ZDHHC13 棕榈酰化，并在自噬诱导时被转运到自噬体形成部位。我们发现，自噬起始需要 ULK1 棕榈酰化。此外，ULK1 的棕榈酰化增强了 ATG14L 的磷酸化，这对于激活 PI3-激酶和产生磷脂酰肌醇 3-磷酸（自噬体膜的脂质之一）是必需的。我们的结果揭示了最上游的 ULK1 复合物在自噬过程中是如何转移到自噬体形成部位的。
