Wong Pui-Mun, Feng Yan, Wang Junru, Shi Rong, Jiang Xuejun
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
Xiangya School of Medicine, Central South University, Hunan 410008, China.
Nat Commun. 2015 Aug 27;6:8048. doi: 10.1038/ncomms9048.
Autophagy is a cellular catabolic process critical for cell viability and homoeostasis. Inhibition of mammalian target of rapamycin (mTOR) complex-1 (mTORC1) activates autophagy. A puzzling observation is that amino acid starvation triggers more rapid autophagy than pharmacological inhibition of mTORC1, although they both block mTORC1 activity with similar kinetics. Here we find that in addition to mTORC1 inactivation, starvation also causes an increase in phosphatase activity towards ULK1, an mTORC1 substrate whose dephosphorylation is required for autophagy induction. We identify the starvation-stimulated phosphatase for ULK1 as the PP2A-B55α complex. Treatment of cells with starvation but not mTORC1 inhibitors triggers dissociation of PP2A from its inhibitor Alpha4. Furthermore, pancreatic ductal adenocarcinoma cells, whose growth depends on high basal autophagy, possess stronger basal phosphatase activity towards ULK1 and require ULK1 for sustained anchorage-independent growth. Taken together, concurrent mTORC1 inactivation and PP2A-B55α stimulation fuel ULK1-dependent autophagy.
自噬是一种对细胞活力和体内平衡至关重要的细胞分解代谢过程。抑制雷帕霉素靶蛋白（mTOR）复合物1（mTORC1）可激活自噬。一个令人困惑的现象是，氨基酸饥饿引发的自噬比mTORC1的药理学抑制更为迅速，尽管它们都以相似的动力学阻断mTORC1活性。在此，我们发现除了mTORC1失活外，饥饿还会导致针对ULK1的磷酸酶活性增加，ULK1是一种mTORC1底物，其去磷酸化是自噬诱导所必需的。我们确定饥饿刺激的针对ULK1的磷酸酶为PP2A-B55α复合物。用饥饿而非mTORC1抑制剂处理细胞会触发PP2A与其抑制剂Alpha4解离。此外，胰腺导管腺癌细胞的生长依赖于高基础自噬，其对ULK1具有更强的基础磷酸酶活性，并且持续的非锚定依赖生长需要ULK1。综上所述，mTORC1的同时失活和PP2A-B55α的刺激促进了ULK1依赖的自噬。
