V-ATPase and osmotic imbalances activate endolysosomal LC3 lipidation
V-ATPase and osmotic imbalances activate endolysosomal LC3 lipidation
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DOI：
10.4161/15548627.2014.984277
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发表时间：
2015-01-01
期刊：
影响因子：
13.3
通讯作者：
Overholtzer, Michael
中科院分区：
文献类型：
--
作者：
Florey, Oliver;Gammoh, Noor;Overholtzer, Michael
最近，自噬蛋白的非经典活性已被发现，其靶向脂质化微管相关蛋白1轻链3（LC 3）到巨内吞空泡，包括巨胞饮体、吞噬体和内吞空泡。虽然这种途径与典型的自噬不同，但这些非自噬膜如何靶向LC 3脂质化的机制仍不清楚。在这里，我们提出的证据表明，这一途径需要活性的液泡型H+-ATP酶（V-ATP酶），并诱导内溶酶体室的渗透压失衡。通过这种机制的LC 3脂质化是通过用亲溶酶体剂氯喹处理细胞以及通过暴露于幽门螺杆菌孔形成毒素VacA来诱导的。这些数据增加了新的机制的见解，非经典的LC 3脂化及其相关过程的调节，包括LC 3相关的吞噬作用（ESTA），并证明，广泛和治疗上使用的药物氯喹，这是传统上用于抑制自噬通量，是LC 3脂化的诱导剂。
Recently a noncanonical activity of autophagy proteins has been discovered that targets lipidation of microtubule-associated protein 1 light chain 3 (LC3) onto macroendocytic vacuoles, including macropinosomes, phagosomes, and entotic vacuoles. While this pathway is distinct from canonical autophagy, the mechanism of how these nonautophagic membranes are targeted for LC3 lipidation remains unclear. Here we present evidence that this pathway requires activity of the vacuolar-type H+-ATPase (V-ATPase) and is induced by osmotic imbalances within endolysosomal compartments. LC3 lipidation by this mechanism is induced by treatment of cells with the lysosomotropic agent chloroquine, and through exposure to the Heliobacter pylori pore-forming toxin VacA. These data add novel mechanistic insights into the regulation of noncanonical LC3 lipidation and its associated processes, including LC3-associated phagocytosis (LAP), and demonstrate that the widely and therapeutically used drug chloroquine, which is conventionally used to inhibit autophagy flux, is an inducer of LC3 lipidation.