PIK3C3/VPS34 control by acetylation
PIK3C3/VPS34 control by acetylation
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DOI：
10.1080/15548627.2017.1385676
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发表时间：
2017-10
期刊：
影响因子：
13.3
通讯作者：
Hua Su;Wei Liu
中科院分区：
文献类型：
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作者：
Hua Su;Wei Liu
摘要PIK 3C 3/VPS 34（磷脂酰肌醇3-激酶催化亚基3型）将磷脂酰肌醇（PtdIns）转化为磷脂酰肌醇-3-磷酸（PtdIns 3 P），维持巨自噬/自噬和内体转运。到目前为止，促进PIK 3C 3/VPS 34-BECN 1-PIK 3R 4/VPS 15/p150核心复合物在不同膜上的组装是激活细胞中PIK 3C 3/VPS 34的唯一已知方式。我们最近揭示了一种调节PIK 3C 3/VPS 34激活的新机制;在营养丰富的条件下，EP 300/p300介导的乙酰化作用抑制了细胞PIK 3C 3/VPS 34。在营养剥夺降低EP 300活性后，PIK 3C 3/VPS 34通过脱乙酰化释放。有趣的是，虽然N-末端K29残基的脱乙酰化导致核心复合物的形成，但C-末端K771位点的脱乙酰化决定了PIK 3C 3/VPS 34与其底物PtdIn的结合。体外和细胞中的证据表明，EP 300依赖性乙酰化和脱乙酰化是关闭/开启PIK 3C 3/VPS 34的开关，其中K771的脱乙酰化是其完全激活所必需的。这种PIK 3C 3/VPS 34激活机制不仅被饥饿诱导的自噬所利用，而且被不涉及AMPK、MTORC 1或ULK 1的自噬所利用。这些发现表明细胞中PIK 3C 3/VPS 34激活的替代回路，其参与响应代谢和非代谢线索的膜转化。
ABSTRACT PIK3C3/VPS34 (phosphatidylinositol 3-kinase catalytic subunit type 3) converts phosphatidylinositol (PtdIns) to phosphatidylinositol-3-phosphate (PtdIns3P), sustaining macroautophagy/autophagy and endosomal transport. So far, facilitating the assembly of the PIK3C3/VPS34-BECN1-PIK3R4/VPS15/p150 core complex at distinct membranes is the only known way to activate PIK3C3/VPS34 in cells. We have recently revealed a novel mechanism that regulates PIK3C3/VPS34 activation; cellular PIK3C3/VPS34 is repressed under nutrient-rich conditions by EP300/p300-mediated acetylation. Following nutrient-deprivation that drops EP300 activity, PIK3C3/VPS34 is liberated by deacetylation. Intriguingly, while deacetylation of the N-terminal K29 residue accounts for core complex formation, deacetylation at the C-terminal K771 site determines the binding of PIK3C3/VPS34 to its substrate PtdIns. In vitro and in cell evidence shows that EP300-dependent acetylation and deacetylation is a switch for turning off/on PIK3C3/VPS34 in which deacetylation of K771 is required for its full activation. This PIK3C3/VPS34 activation mechanism is utilized not only by starvation-induced autophagy but also by autophagy without the involvement of AMPK, MTORC1 or ULK1. These findings suggest an alternative circuit in cells for PIK3C3/VPS34 activation, which is involved in membrane transformations in response to metabolic and nonmetabolic cues.