Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Nat Commun. 2021 Nov 19;12(1):6750. doi: 10.1038/s41467-021-26999-x.
The multispanning membrane protein ATG9A is a scramblase that flips phospholipids between the two membrane leaflets, thus contributing to the expansion of the phagophore membrane in the early stages of autophagy. Herein, we show that depletion of ATG9A does not only inhibit autophagy but also increases the size and/or number of lipid droplets in human cell lines and C. elegans. Moreover, ATG9A depletion blocks transfer of fatty acids from lipid droplets to mitochondria and, consequently, utilization of fatty acids in mitochondrial respiration. ATG9A localizes to vesicular-tubular clusters (VTCs) that are tightly associated with an ER subdomain enriched in another multispanning membrane scramblase, TMEM41B, and also in close proximity to phagophores, lipid droplets and mitochondria. These findings indicate that ATG9A plays a critical role in lipid mobilization from lipid droplets to autophagosomes and mitochondria, highlighting the importance of ATG9A in both autophagic and non-autophagic processes.
多跨膜蛋白 ATG9A 是一种翻转酶，可将磷脂在两个膜小叶之间翻转，从而有助于自噬早期吞噬体膜的扩展。在此，我们表明 ATG9A 的耗竭不仅会抑制自噬，还会增加人细胞系和秀丽隐杆线虫中脂滴的大小和/或数量。此外，ATG9A 的耗竭会阻止脂肪酸从脂滴转移到线粒体，从而影响线粒体呼吸中脂肪酸的利用。ATG9A 定位于囊泡管状簇 (VTCs)，这些 VTCs与富含另一种多跨膜翻转酶 TMEM41B 的内质网亚域紧密相关，并且还与吞噬体、脂滴和线粒体接近。这些发现表明 ATG9A 在从脂滴向自噬体和线粒体转运脂质中发挥关键作用，突出了 ATG9A 在自噬和非自噬过程中的重要性。
