a Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai , China.
b University of the Chinese Academy of Sciences , Shanghai , China.
Autophagy. 2016 Sep;12(9):1447-59. doi: 10.1080/15548627.2016.1185576. Epub 2016 Jun 15.
Macroautophagy/autophagy is a conserved catabolic process that recycles cytoplasmic material during low energy conditions. BECN1/Beclin1 (Beclin 1, autophagy related) is an essential protein for function of the class 3 phosphatidylinositol 3-kinase (PtdIns3K) complexes that play a key role in autophagy nucleation and elongation. Here, we show that AMP-activated protein kinase (AMPK) regulates autophagy by phosphorylating BECN1 at Thr388. Phosphorylation of BECN1 is required for autophagy upon glucose withdrawal. BECN1(T388A), a phosphorylation defective mutant, suppresses autophagy through decreasing the interaction between PIK3C3 (phosphatidylinositol 3-kinase catalytic subunit type 3) and ATG14 (autophagy-related 14). The BECN1(T388A) mutant has a higher affinity for BCL2 than its wild-type counterpart; the mutant is more prone to dimer formation. Conversely, a BECN1 phosphorylation mimic mutant, T388D, has stronger binding to PIK3C3 and ATG14, and promotes higher autophagy activity than the wild-type control. These findings uncover a novel mechanism of autophagy regulation.
自噬是一种保守的分解代谢过程，在能量较低的情况下回收细胞质物质。BECN1/Beclin1（Beclin 1，自噬相关）是一种必不可少的蛋白，对于发挥关键作用的 III 类磷酸肌醇 3-激酶（PtdIns3K）复合物的功能至关重要，这些复合物在自噬核的形成和延伸中起作用。在这里，我们表明 AMP 激活的蛋白激酶（AMPK）通过磷酸化 BECN1 的 Thr388 来调节自噬。BECN1 的磷酸化是葡萄糖剥夺后自噬所必需的。BECN1(T388A)，一种磷酸化缺陷突变体，通过降低 PIK3C3（磷酸肌醇 3-激酶催化亚基类型 3）和 ATG14（自噬相关 14）之间的相互作用来抑制自噬。与野生型相比，BECN1(T388A)突变体与 BCL2 的亲和力更高；突变体更容易形成二聚体。相反，BECN1 磷酸化模拟突变体 T388D 与 PIK3C3 和 ATG14 的结合更强，并促进比野生型对照更高的自噬活性。这些发现揭示了自噬调节的一种新机制。
