AMPK regulates autophagy by phosphorylating BECN1 at threonine 388.
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.
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.
Deyi
D
Zhang
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.
Wei
W
Wang
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.
Xiujie
X
Sun
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.
Daqian
D
Xu
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.
Chenyao
C
Wang
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.
Qian
Q
Zhang
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.
Huafei
H
Wang
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.
Wenwen
W
Luo
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.
Yan
Y
Chen
c Tianjin Haihe Hospital, Tianjin Institute of Respiratory Diseases , Tianjin , China.
Huaiyong
H
Chen
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.
Zhixue
Z
Liu
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1 / Q000378:metabolism*; D002384:Catalysis; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000737:chemistry; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009154:Mutation; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010766:Phosphorylation; D055503:Protein Multimerization; D013912:Threonine / Q000737:chemistry
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D008565:Membrane Proteins; D018129:Phosphatidylinositol Phosphates; C055525:phosphatidylinositol 3-phosphate; D013912:Threonine; D058546:Class III Phosphatidylinositol 3-Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose
AMPK; BECN1; autophagy; phosphorylation; regulation