VPS34 Acetylation Controls Its Lipid Kinase Activity and the Initiation of Canonical and Non-canonical Autophagy
VPS34 Acetylation Controls Its Lipid Kinase Activity and the Initiation of Canonical and Non-canonical Autophagy
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VPS34 乙酰化控制其脂质激酶活性以及经典和非经典自噬的启动
DOI：
10.1016/j.molcel.2017.07.024
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发表时间：
2017-09-21
期刊：
影响因子：
16
通讯作者：
Liu, Wei
中科院分区：
文献类型：
--
作者：
Su, Hua;Yang, Fei;Liu, Wei
III型磷脂酰肌醇3-激酶Vps34在囊泡运输和大自噬的调节中起着关键作用。到目前为止，除了与调节蛋白相互作用形成复合体外，我们对Vps34激活的分子机制知之甚少。在这里，我们报道了Vps34被乙酰基转移酶p300特异性乙酰化，而p300介导的乙酰化抑制了Vps34的活性。K771位的乙酰化直接降低了Vps34与底物PI的亲和力，而K29位的乙酰化阻碍了Vps34-Beclin 1核心复合体的形成。即使在AMPK(-/-)、TSC2(-/-)或ULK1(-/-)细胞中，p300的失活也会诱导Vps34去乙酰化、PI3P的产生和自噬。在禁食小鼠中，肝脏自噬与p300失活/Vps34去乙酰化有很好的相关性，这有助于清除肝细胞中的脂滴。因此，依赖于p300的Vps34乙酰化/去乙酰化是Vps34激活的生理关键，它控制着典型自噬和非典型自噬的启动，在非典型自噬中，Vps34的上游激酶可以被绕过。
The class III phosphoinositide 3-kinase VPS34 plays a key role in the regulation of vesicular trafficking and macroautophagy. So far, we know little about the molecular mechanism of VPS34 activation besides its interaction with regulatory proteins to form complexes. Here, we report that VPS34 is specifically acetylated by the acetyltransferase p300, and p300-mediated acetylation represses VPS34 activity. Acetylation at K771 directly diminishes the affinity of VPS34 for its substrate PI, while acetylation at K29 hinders the VPS34-Beclin 1 core complex formation. Inactivation of p300 induces VPS34 deacetylation, PI3P production, and autophagy, even in AMPK(-/-), TSC2(-/-), or ULK1(-/-) cells. In fasting mice, liver autophagy correlates well with p300 inactivation/VPS34 deacetylation, which facilitates the clearance of lipid droplets in hepatocytes. Thus, p300-dependent VPS34 acetylation/deacetylation is the physiological key to VPS34 activation, which controls the initiation of canonical autophagy and of non-canonical autophagy in which the upstream kinases of VPS34 can be bypassed.