Journal Article

Palmitoylation of ULK1 by ZDHHC13 plays a crucial role in autophagy

Imai, Kenta, Tischer, Christian, Fujita, Toshiharu, Yoshimori, Tamotsu, Hamasaki, Maho, Kaminishi, Tatsuya, Verissimo, Fatima, Fukuda, Koki, Reither, Sabine, Pepperkok, Rainer, Tabata, Keisuke, Neumann, Beate, Yamamoto, Kentaro, Kunugi, Hayato

2024

Overview

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. It was unknown how the most upstream Atg protein transits from the cytosol to autophagosome formation sites. Here, the authors show that ULK1 palmitoylation by ZDHHC13 recruits the complex to the formation site and enhances ATG14L phosphorylation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 1-Phosphatidylinositol 3-kinase / 14 / 14/63 / 49 / 631/80/39 / 631/80/458 / 631/80/642/2384 / 82/1 / 82/51 / 82/80 / 82/83 / Acyltransferases - genetics / Acyltransferases - metabolism / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Adaptor Proteins, Vesicular Transport - genetics / Adaptor Proteins, Vesicular Transport - metabolism / Animals / Autophagosomes - metabolism / Autophagy / Autophagy - physiology / Autophagy-Related Protein-1 Homolog - genetics / Autophagy-Related Protein-1 Homolog - metabolism / Autophagy-Related Proteins - genetics / Autophagy-Related Proteins - metabolism / Cytosol / Genetic analysis / HEK293 Cells / Humanities and Social Sciences / Humans / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / Kinases / Lipids / Lipoylation / Membranes / multidisciplinary / Palmitoylation / Palmitoyltransferase / Phosphatidylinositol 3-phosphate / Phosphatidylinositol Phosphates - metabolism / Phosphorylation / Protein Transport / Proteins / Science / Science (multidisciplinary) / Translocation / Upstream / Vesicular Transport Proteins / Yeast