Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK

Chen-Song Zhang, Simon A. Hawley, Yue Zong, Mengqi Li, Zhichao Wang, Alexander Gray, Teng Ma, Jiwen Cui, Jin-Wei Feng, Mingjiang Zhu, Yu-Qing Wu, Terytty Yang Li, Zhiyun Ye, Shu-Yong Lin, Huiyong Yin, Hai-Long Piao, D. Grahame Hardie (Lead / Corresponding author), Sheng-Cai Lin (Lead / Corresponding author)

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Abstract

The major energy source for most cells is glucose, from which ATP is generated via glycolysis and/or oxidative metabolism. Glucose deprivation activates AMP-activated protein kinase (AMPK), but it is unclear whether this activation occurs solely via changes in AMP or ADP, the classical activators of AMPK. Here, we describe an AMP/ADP-independent mechanism that triggers AMPK activation by sensing the absence of fructose-1,6-bisphosphate (FBP), with AMPK being progressively activated as extracellular glucose and intracellular FBP decrease. When unoccupied by FBP, aldolases promote the formation of a lysosomal complex containing at least v-ATPase, ragulator, axin, liver kinase B1 (LKB1) and AMPK, which has previously been shown to be required for AMPK activation. Knockdown of aldolases activates AMPK even in cells with abundant glucose, whereas the catalysis-defective D34S aldolase mutant, which still binds FBP, blocks AMPK activation. Cell-free reconstitution assays show that addition of FBP disrupts the association of axin and LKB1 with v-ATPase and ragulator. Importantly, in some cell types AMP/ATP and ADP/ATP ratios remain unchanged during acute glucose starvation, and intact AMP-binding sites on AMPK are not required for AMPK activation. These results establish that aldolase, as well as being a glycolytic enzyme, is a sensor of glucose availability that regulates AMPK.

Original languageEnglish
Pages (from-to)112-116
Number of pages23
JournalNature
Volume548
Issue number7665
Early online date19 Jul 2017
DOIs
Publication statusPublished - 3 Aug 2017

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Fructose-Bisphosphate Aldolase
AMP-Activated Protein Kinases
Glucose
Adenosine Monophosphate
Adenosine Diphosphate
Adenosine Triphosphate
Adenosine Triphosphatases
Aldehyde-Lyases
Liver
Glycolysis
Starvation
Catalysis
Phosphotransferases
Binding Sites

Keywords

  • Nutrient signalling
  • Molecular biology

Cite this

Zhang, Chen-Song ; Hawley, Simon A. ; Zong, Yue ; Li, Mengqi ; Wang, Zhichao ; Gray, Alexander ; Ma, Teng ; Cui, Jiwen ; Feng, Jin-Wei ; Zhu, Mingjiang ; Wu, Yu-Qing ; Li, Terytty Yang ; Ye, Zhiyun ; Lin, Shu-Yong ; Yin, Huiyong ; Piao, Hai-Long ; Hardie, D. Grahame ; Lin, Sheng-Cai. / Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK. In: Nature. 2017 ; Vol. 548, No. 7665. pp. 112-116.
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abstract = "The major energy source for most cells is glucose, from which ATP is generated via glycolysis and/or oxidative metabolism. Glucose deprivation activates AMP-activated protein kinase (AMPK), but it is unclear whether this activation occurs solely via changes in AMP or ADP, the classical activators of AMPK. Here, we describe an AMP/ADP-independent mechanism that triggers AMPK activation by sensing the absence of fructose-1,6-bisphosphate (FBP), with AMPK being progressively activated as extracellular glucose and intracellular FBP decrease. When unoccupied by FBP, aldolases promote the formation of a lysosomal complex containing at least v-ATPase, ragulator, axin, liver kinase B1 (LKB1) and AMPK, which has previously been shown to be required for AMPK activation. Knockdown of aldolases activates AMPK even in cells with abundant glucose, whereas the catalysis-defective D34S aldolase mutant, which still binds FBP, blocks AMPK activation. Cell-free reconstitution assays show that addition of FBP disrupts the association of axin and LKB1 with v-ATPase and ragulator. Importantly, in some cell types AMP/ATP and ADP/ATP ratios remain unchanged during acute glucose starvation, and intact AMP-binding sites on AMPK are not required for AMPK activation. These results establish that aldolase, as well as being a glycolytic enzyme, is a sensor of glucose availability that regulates AMPK.",
keywords = "Nutrient signalling, Molecular biology",
author = "Chen-Song Zhang and Hawley, {Simon A.} and Yue Zong and Mengqi Li and Zhichao Wang and Alexander Gray and Teng Ma and Jiwen Cui and Jin-Wei Feng and Mingjiang Zhu and Yu-Qing Wu and Li, {Terytty Yang} and Zhiyun Ye and Shu-Yong Lin and Huiyong Yin and Hai-Long Piao and Hardie, {D. Grahame} and Sheng-Cai Lin",
note = "D.G.H. was supported by an Investigator Award from the Wellcome Trust (097726) and a Programme Grant from Cancer Research UK (C37030/A15101). S.-C.L. was supported by grants from the National Key Research and Development Project of China (2016YFA0502001) and the National Natural Science Foundation of China (#31430094, #31690101, #31571214, #31601152 and #J1310027).",
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Zhang, C-S, Hawley, SA, Zong, Y, Li, M, Wang, Z, Gray, A, Ma, T, Cui, J, Feng, J-W, Zhu, M, Wu, Y-Q, Li, TY, Ye, Z, Lin, S-Y, Yin, H, Piao, H-L, Hardie, DG & Lin, S-C 2017, 'Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK', Nature, vol. 548, no. 7665, pp. 112-116. https://doi.org/10.1038/nature23275

Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK. / Zhang, Chen-Song; Hawley, Simon A.; Zong, Yue; Li, Mengqi; Wang, Zhichao; Gray, Alexander; Ma, Teng; Cui, Jiwen; Feng, Jin-Wei; Zhu, Mingjiang; Wu, Yu-Qing; Li, Terytty Yang; Ye, Zhiyun; Lin, Shu-Yong; Yin, Huiyong; Piao, Hai-Long; Hardie, D. Grahame (Lead / Corresponding author); Lin, Sheng-Cai (Lead / Corresponding author).

In: Nature, Vol. 548, No. 7665, 03.08.2017, p. 112-116.

Research output: Contribution to journalLetter

TY - JOUR

T1 - Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK

AU - Zhang, Chen-Song

AU - Hawley, Simon A.

AU - Zong, Yue

AU - Li, Mengqi

AU - Wang, Zhichao

AU - Gray, Alexander

AU - Ma, Teng

AU - Cui, Jiwen

AU - Feng, Jin-Wei

AU - Zhu, Mingjiang

AU - Wu, Yu-Qing

AU - Li, Terytty Yang

AU - Ye, Zhiyun

AU - Lin, Shu-Yong

AU - Yin, Huiyong

AU - Piao, Hai-Long

AU - Hardie, D. Grahame

AU - Lin, Sheng-Cai

N1 - D.G.H. was supported by an Investigator Award from the Wellcome Trust (097726) and a Programme Grant from Cancer Research UK (C37030/A15101). S.-C.L. was supported by grants from the National Key Research and Development Project of China (2016YFA0502001) and the National Natural Science Foundation of China (#31430094, #31690101, #31571214, #31601152 and #J1310027).

PY - 2017/8/3

Y1 - 2017/8/3

N2 - The major energy source for most cells is glucose, from which ATP is generated via glycolysis and/or oxidative metabolism. Glucose deprivation activates AMP-activated protein kinase (AMPK), but it is unclear whether this activation occurs solely via changes in AMP or ADP, the classical activators of AMPK. Here, we describe an AMP/ADP-independent mechanism that triggers AMPK activation by sensing the absence of fructose-1,6-bisphosphate (FBP), with AMPK being progressively activated as extracellular glucose and intracellular FBP decrease. When unoccupied by FBP, aldolases promote the formation of a lysosomal complex containing at least v-ATPase, ragulator, axin, liver kinase B1 (LKB1) and AMPK, which has previously been shown to be required for AMPK activation. Knockdown of aldolases activates AMPK even in cells with abundant glucose, whereas the catalysis-defective D34S aldolase mutant, which still binds FBP, blocks AMPK activation. Cell-free reconstitution assays show that addition of FBP disrupts the association of axin and LKB1 with v-ATPase and ragulator. Importantly, in some cell types AMP/ATP and ADP/ATP ratios remain unchanged during acute glucose starvation, and intact AMP-binding sites on AMPK are not required for AMPK activation. These results establish that aldolase, as well as being a glycolytic enzyme, is a sensor of glucose availability that regulates AMPK.

AB - The major energy source for most cells is glucose, from which ATP is generated via glycolysis and/or oxidative metabolism. Glucose deprivation activates AMP-activated protein kinase (AMPK), but it is unclear whether this activation occurs solely via changes in AMP or ADP, the classical activators of AMPK. Here, we describe an AMP/ADP-independent mechanism that triggers AMPK activation by sensing the absence of fructose-1,6-bisphosphate (FBP), with AMPK being progressively activated as extracellular glucose and intracellular FBP decrease. When unoccupied by FBP, aldolases promote the formation of a lysosomal complex containing at least v-ATPase, ragulator, axin, liver kinase B1 (LKB1) and AMPK, which has previously been shown to be required for AMPK activation. Knockdown of aldolases activates AMPK even in cells with abundant glucose, whereas the catalysis-defective D34S aldolase mutant, which still binds FBP, blocks AMPK activation. Cell-free reconstitution assays show that addition of FBP disrupts the association of axin and LKB1 with v-ATPase and ragulator. Importantly, in some cell types AMP/ATP and ADP/ATP ratios remain unchanged during acute glucose starvation, and intact AMP-binding sites on AMPK are not required for AMPK activation. These results establish that aldolase, as well as being a glycolytic enzyme, is a sensor of glucose availability that regulates AMPK.

KW - Nutrient signalling

KW - Molecular biology

U2 - 10.1038/nature23275

DO - 10.1038/nature23275

M3 - Letter

C2 - 28723898

VL - 548

SP - 112

EP - 116

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7665

ER -