WIPI3 and WIPI4 β-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy.
WIPI3 and WIPI4 β-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy.
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DOI：
10.1038/ncomms15637
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发表时间：
2017-05-31
影响因子：
16.6
通讯作者：
Proikas-Cezanne T
中科院分区：
文献类型：
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作者：
Bakula D;Müller AJ;Zuleger T;Takacs Z;Franz-Wachtel M;Thost AK;Brigger D;Tschan MP;Frickey T;Robenek H;Macek B;Proikas-Cezanne T
自噬由AMPK和mTOR控制，这两者都与ULK 1相关，并控制磷脂酰肌醇3-磷酸（PtdIns 3 P）的产生，这是自噬体形成的先决条件。在这里，我们报告说，WIPI 3和WIPI 4支架PtdIns 3 P生产的自噬上游的信号控制，并在新生的自噬体WIPI 1-WIPI 2的PtdIns 3 P效应器功能中发挥作用。响应于LKB 1介导的AMPK刺激，WIPI 4-ATG 2从WIPI 4-ATG 2/AMPK-ULK 1复合物中释放，并易位到新生的自噬体，控制它们的大小，WIPI 3与FIP 200复合也有助于其形成。在上游，WIPI 3在溶酶体处与AMPK活化的TSC复合物结合，调节mTOR。我们的WIPI相互作用组分析揭示了WIPI蛋白的支架功能，其将自噬信号控制和自噬体形成相互连接。我们的功能性激酶筛选揭示了LKB 1介导的AMPK刺激之间的一种新的调节联系，该刺激通过WIPI 4产生直接信号，我们表明AMPK相关激酶NUAK 2和BRSK 2通过WIPI 4调节自噬。在自噬过程中，AMPK和mTOR与ULK 1结合并调节磷脂酰肌醇3-磷酸（PtdIns 3 P）的产生，后者通过WIPI蛋白介导自噬体的形成。在这里，作者表明WIPI 3和WIPI 4在PtdIns 3 P产生的上游具有支架功能，并且在新生自噬体中WIPI 1-WIPI 2的PtdIns 3 P效应子功能中具有作用。
Autophagy is controlled by AMPK and mTOR, both of which associate with ULK1 and control the production of phosphatidylinositol 3-phosphate (PtdIns3P), a prerequisite for autophagosome formation. Here we report that WIPI3 and WIPI4 scaffold the signal control of autophagy upstream of PtdIns3P production and have a role in the PtdIns3P effector function of WIPI1-WIPI2 at nascent autophagosomes. In response to LKB1-mediated AMPK stimulation, WIPI4-ATG2 is released from a WIPI4-ATG2/AMPK-ULK1 complex and translocates to nascent autophagosomes, controlling their size, to which WIPI3, in complex with FIP200, also contributes. Upstream, WIPI3 associates with AMPK-activated TSC complex at lysosomes, regulating mTOR. Our WIPI interactome analysis reveals the scaffold functions of WIPI proteins interconnecting autophagy signal control and autophagosome formation. Our functional kinase screen uncovers a novel regulatory link between LKB1-mediated AMPK stimulation that produces a direct signal via WIPI4, and we show that the AMPK-related kinases NUAK2 and BRSK2 regulate autophagy through WIPI4. During autophagy, AMPK and mTOR associate with ULK1 and regulate phosphatidylinositol 3-phosphate (PtdIns3P) production that mediates autophagosome formation via WIPI proteins. Here the authors show WIPI3 and WIPI4 have a scaffolding function upstream of PtdIns3P production and have a role in the PtdIns3P effector function of WIPI1-WIPI2 at nascent autophagosomes.