Millard Emily, Tooze Sharon A
Molecular Cell Biology of Autophagy, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
Molecular Cell Biology of Autophagy, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
J Mol Biol. 2025 Sep 15;437(18):169288. doi: 10.1016/j.jmb.2025.169288. Epub 2025 Jun 11.
Autophagy proteins coordinate the biogenesis of a phagophore, the formation and maturation of an autophagosome. Genetic mutations of these proteins can result in dysregulated autophagy, stalled autophagosome biogenesis, and lead to cell death. ATG9, the sole transmembrane ATG (autophagy related) protein governs the nucleation of the phagophore. At a molecular level ATG9 has been shown to be a lipid scramblase capable of redistributing lipids across the lipid bilayer. ATG9-positive vesicles can also deliver lipid-modifying enzymes to alter the lipid composition of membranes. Both functions are required for autophagy. However, ATG proteins, including ATG9, play key molecular roles in pathways unrelated to autophagy. ATG9 has been shown to function in multiple pathways at the Golgi, plasma membrane, and lysosomes. ATG9 can also play an important role in immune signalling. The trafficking of ATG9 in ATG9-positive vesicles is essential to many of these pathways. In this review we highlight the functions of ATG9 in autophagy and autophagy-unrelated pathways, here referred to as "non-canonical functions", and summarise the broader role of ATG9A in cell homeostasis.
自噬蛋白协调吞噬泡的生物发生、自噬体的形成和成熟。这些蛋白的基因突变可导致自噬失调、自噬体生物发生停滞，并导致细胞死亡。ATG9是唯一的跨膜自噬相关蛋白，它控制着吞噬泡的成核。在分子水平上，ATG9已被证明是一种脂质翻转酶，能够在脂质双分子层中重新分布脂质。ATG9阳性囊泡还可以传递脂质修饰酶，以改变膜的脂质组成。这两种功能都是自噬所必需的。然而，包括ATG9在内的自噬相关蛋白在与自噬无关的途径中发挥着关键的分子作用。ATG9已被证明在高尔基体、质膜和溶酶体的多种途径中发挥作用。ATG9在免疫信号传导中也可以发挥重要作用。ATG9在ATG9阳性囊泡中的运输对许多这些途径至关重要。在这篇综述中，我们重点介绍了ATG9在自噬和与自噬无关的途径（这里称为“非经典功能”）中的功能，并总结了ATG9A在细胞稳态中的更广泛作用。
