Abstract
The mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth in response to amino acid and glucose levels. However, how mTORC1 senses glucose availability to regulate various downstream signalling pathways remains largely elusive. Here we report that AMP-activated protein kinase (AMPK)-mediated phosphorylation of WDR24, a core component of the GATOR2 complex, has a role in the glucose-sensing capability of mTORC1. Mechanistically, glucose deprivation activates AMPK, which directly phosphorylates WDR24 on S155, subsequently disrupting the integrity of the GATOR2 complex to suppress mTORC1 activation. Phosphomimetic Wdr24S155D knock-in mice exhibit early embryonic lethality and reduced mTORC1 activity. On the other hand, compared to wild-type littermates, phospho-deficient Wdr24S155A knock-in mice are more resistant to fasting and display elevated mTORC1 activity. Our findings reveal that AMPK-mediated phosphorylation of WDR24 modulates glucose-induced mTORC1 activation, thereby providing a rationale for targeting AMPK–WDR24 signalling to fine-tune mTORC1 activation as a potential therapeutic means to combat human diseases with aberrant activation of mTORC1 signalling including cancer.
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Data availability
All data that support the findings of this study are available in the figures or Extended Data figures. Mass spectrometry fragmentation spectra were searched against the concatenated decoy human protein database v.20210315 (UniProt). Source data are provided with this paper.
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Acknowledgements
We thank J. Liu, F. Dang and other Wei laboratory members for critical reading of the manuscript, as well as members of the Wei and Guo laboratories for helpful discussions. This work was supported in part by National Institutes of Health grant nos. R01CA177910 and R35CA253027 to W.W., no. 1K99CA259329 to X.D., no. P01CA120964 to J.A. and the China National Natural Science Foundation (nos. 31871410 and 32070767 to J.G. and no. 32100559 to Q.J.).
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X.D. and C.J. designed and performed most of the experiments with assistance from Q.J., P.Y., F.C., T.Z., H.I. and J.M.A. Q.J., L.F., H.Y. and Jinhe Guo helped with mouse generation and phenotype analysis. P.W., Jianping Guo and W.W. guided and supervised the study. X.D., C.J., Jianping Guo and W.W. wrote the manuscript. All authors commented on the manuscript.
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W.W. is a co-founder and consultant for ReKindle Therapeutics. The other authors declare no competing interests.
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Extended data
Extended Data Fig. 1 GATOR1/2 complexes play an important role in mTORC1 glucose sensing.
a, WT and NPRL2 knockout (KO) HeLa cells were deprived of glucose (Glc) for 60 min and restimulated with glucose for 10 min as indicated. WCLs were analyzed via IB. b,c, WT and NPRL2 KO HEK 293 (b) or HeLa (c) cells were deprived of amino acids (AA) for 60 min and restimulated with amino acids for 10 min as indicated. d, IB analysis of WCLs derived from WT and WDR24 KO HeLa cells. The cells were treated as in (a). e,f, WT and WDR24 KO HEK 293 (e) or HeLa (f) cells were deprived of amino acids for 60 min and restimulated with amino acids for 10 min as indicated. g, WDR24 KO HEK 293 cells were re-introduced with or without WT WDR24, and the resulting cells were treated as in (d). h,i, WT and NPRL2 KO HeLa cells were deprived of glucose for 60 min and restimulated with glucose for 10 min before coimmunostaining for mTOR (red) and LAMP1 (green) (h). Scale bar, 10 μm. The imaging data were quantified (i). n = 10. P = 4.93E-07, 0.21. Data are the mean ± s.d., two-tailed t-test. NS, not significant, ***P < 0.001. j,k, WT and WDR24 KO HeLa cells were treated as in (h,i). The imaging data were quantified (k). Scale bar, 10 μm. n = 10. P = 1.12E-09, 0.90. Data are the mean ± s.d., two-tailed t-test. NS, not significant, ***P < 0.001. Representative image shown, a and d, n = 3; b, c, e, f and g, n = 2.
Extended Data Fig. 2 AMPK plays a pivotal role in mTORC1 glucose sensing.
a, IB analysis of WCLs derived from WT and AMPKα1/2 double knockout (DKO) HEK 293 cells. The cells were deprived of glucose for 60 min and restimulated with glucose for 10 min as indicated. b, IB analysis of WCLs derived from WT and AMPKα1/2 DKO HEK 293 T cells. The cells were deprived of glucose or amino acids for 60 min and restimulated with glucose or amino acids for 10 min as indicated. c, IB analysis of WCLs derived from WT and Ampkα1/2 DKO MEFs. The cells were treated as in (a). d, IB analysis of WCLs derived from WT, AMPKα1/2 DKO, AMPKα1 and AMPKα2 reconstituted AMPKα1/2 DKO U2OS cells. The cells were treated as in (a). e,f, HEK 293 cells were treated with or without A-769662 (100 μM) for 60 min, and the co-localization of mTORC1 (Red) and LAMP1 (green) was analyzed via immunofluorescence (e). Scale bar, 10 μm. The imaging data were quantified (f). n = 17, 20. P = 0.00058. Data are the mean ± s.d., two-tailed t-test. NS, not significant, ***P < 0.001. Representative image shown, a, b and d, n = 2; c, n = 3.
Extended Data Fig. 3 AMPK interacts with and phosphorylates WDR24.
a, IB analysis of WCLs and anti-Flag IPs derived from WT and WDR24 Flag knockin (KI) HEK 293 cells. b,c, IB analysis of WCLs and anti-HA or anti-Flag IPs derived from 293 T cells transfected with the indicated constructs. d, IB analysis of WCLs and anti-HA IPs derived from 293 T cells transfected with the indicated constructs. The cells were deprived of glucose for 60 min and restimulated with glucose for 10 min before harvesting. e,f, IB analysis of WCLs and anti-HA IPs derived from WDR59 (e) or Mios (f) KO HEK 293 cells transfected with the indicated constructs. g, IB analysis of WCLs and GST-Pull down derived from WDR24 KO HEK 293 cells transfected with the indicated constructs. h, Bacterial purified GST-WDR24 fragments were incubated with full-length human AMPK (combination of A1/B1/G2 subunits) which was expressed by baculovirus in Sf9 insect cells using a C-terminal His tag (SignalChem) for 3 h at 4 °C. i, IB analysis of WCLs and GST-Pull down derived from WDR24 KO HEK 293 cells transfected with the indicated constructs. j, In vitro kinase assay of indicated proteins demonstrates that AMPK phosphorylates WDR24. GST-WDR24 and YAP1 proteins were bacterially purified as substrates, and recombinant active AMPK was used as the source of kinase. Anti-thiophosphate-ester antibody was used to detect phosphorylated proteins. GST-YAP1 as a positive control. Representative image shown, a, n = 3; b-j, n = 2.
Extended Data Fig. 4 AMPK phosphorylates WDR24 on the S155 residue.
a, Scansite shows that WDR24 has a possible AMPK phosphorylation site. b, The MS/MS fragmentation spectrum showing fragment ions for the WDR24 peptide KDpSVSTFSGQSESV defining the WDR24-pS155 site. c, Titration of the indicated WDR24 peptides with or without S155 phosphorylation demonstrates that the generated WDR24-pS155 antibodies specifically recognize the pS155 epitope in the dot blot analysis. d, IB analysis of anti-Flag IPs derived from 293 T cells transfected with indicated constructs to demonstrate that mutating the Ser155 site in WDR24 abolished the ability of the generated WDR24-pS155 antibody (#3 and #5) to recognize WDR24 phosphorylated species in cells. e, In vitro kinase assays demonstrated that the WDR24-pS155 antibody recognizes the phosphorylated WDR24. GST-WDR24 protein was purified from E. coli, and recombinant active AMPK was used as the source of kinase. f, IB analysis of WCLs and anti-Flag IPs derived from WT and WDR24 Flag knock-in HEK 293 cells. The cells were deprived of glucose for 60 min and restimulated with glucose for 10 min as indicated. g, WDR24 KO HEK 293 cells reconstituted with WT-WDR24 were starved of glucose and treated with Compound C (10 μM) for 1 h before harvesting for IB analysis. h, IB analysis of WCLs and anti-HA IPs derived from WT or AMPKα1/2 DKO HEK 293 T cells transfected with indicated constructs. The cells were deprived of glucose for 60 min and restimulated with glucose for 10 min as indicated. i, IB analysis of WCLs and anti-Flag IPs derived from WDR24 KO HEK 293 cells reconstituted with indicated constructs. Representative image shown, e-i, n = 2.
Extended Data Fig. 5 Phosphorylation of S155 on WDR24 inhibits the activation of mTORC1 induced by glucose.
a, WDR24 KO HeLa cells re-introduced with indicated constructs were deprived of glucose for 60 min and restimulated with glucose for 10 min as indicated. b, Cell size histogram of WDR24 KO HeLa cells reconstituted with WT and WDR24 S155D by FACS. c, WDR24 KO HeLa cells reconstituted with indicated constructs were plated for 8 d for the colony-formation assays. Data are shown as the mean ± s.d. of n = 3 independent experiments (bottom). P = 0.0004. two-tailed t-test. ***P < 0.001. d, IB analysis of WCLs of HEK 293 cells starved of glucose or/and amino acids for 1 h, and restimulated with amino acids for 10 min. e, WDR24 KO HEK 293 cells re-introduced with indicated constructs were deprived of amino acids for 60 min and restimulated with amino acids for 10 min as indicated before IB analysis. f, WDR24 KO HeLa cells were re-introduced with indicated constructs. The cells were treated as in (e). g,h, WT and AMPKα1/2 DKO HEK 293 (g) or 293 T (h) cells were starved of amino acids or amino acids and glucose together for 60 min, then stimulated with amino acids for 10 min. i, Working model to show how AMPK regulates mTORC1 amino acid sensing under energy stress conditions. Representative image shown, a and d, n = 3; e, f, g and h, n = 2.
Extended Data Fig. 6 The WDR24-S155D mutation inhibits mTORC1 kinase activity.
a, Schematic representation of the amino sequence to generate WDR24-S155D CRISPR knock-in cells. b, Identification of the potential knock-in mutants. Genomic DNA containing WDR24-S155D mutation was amplified by PCR and digested with BslI. c, Confirmation of the correct mutation of Raptor-S606D or S606A by Sanger DNA sequencing. d, WT and WDR24-S155D knock-in 293 cells were deprived of amino acids for 60 min and restimulated with amino acids for 10 min as indicated. Representative image shown, n = 3. e, WT and WDR24-S155D knock-in 293 cells were deprived of glucose for 60 min and restimulated with glucose for 10 min before immunostaining for mTOR and LAMP1. The imaging data were quantified under each condition. n = 17, 16, 16, 15. P = 5.67E-06, 0.11. Data are the mean ± s.d., two-tailed t-test. NS, not significant, ***P < 0.001. See Fig. 4e for imaging data. f,g, WT and WDR24-S155D knock-in 293 cells were deprived of amino acids for 60 min and restimulated with amino acids for 10 min before coimmunostaining for mTOR (red) and LAMP1 (green) (f). Scale bar, 10 μm. The imaging data were quantified with 10-20 cells under each condition (g). n = 19, 18, 15, 18. P = 2.56E-13, 0.08. Data are the mean ± s.d., two-tailed t-test. NS, not significant. ***P < 0.001. h, IB analysis of WCLs and anti-HA IPs derived from WT and WDR24-S155D knock-in HEK 293 cells transfected with the indicated constructs. The cells were deprived of glucose for 60 min and restimulated with glucose for 10 min before harvesting. Representative image shown, n = 2.
Extended Data Fig. 7 Glucose deprivation regulates GATOR2 complex integrity through phosphorylating WDR24 on S155.
a, IB analysis of WCLs and anti-Flag IPs derived from WDR24 KO HEK 293 cells reconstituted with indicated constructs. The cells were deprived of glucose for 60 min and restimulated with glucose for different time points as indicated. b, WCLs of HEK 293 cells deprived of glucose for 60 min and restimulated with glucose for 10 min as indicated were run through a Superose 6 Increase 10/300 GL column. Elutes were collected for each fraction and analyzed by IB analysis. c, WCLs of HEK 293 cells were deprived of amino acids for 60 min and restimulated with amino acids for 10 min as indicated and analyzed as (b). d, IB analysis of WCLs and anti-Flag IPs derived from WDR24 KO HEK 293 cells reconstituted with indicated constructs. The cells were deprived of amino acids for 60 min and restimulated with amino acids for 10 min as indicated. e, IB analysis of WCLs and anti-Flag IPs derived from WDR24 KO HEK 293 cells reconstituted with indicated constructs. Cells were starved with amino acids or amino acids and glucose together for 60 min, then stimulated with amino acids for 10 min. f,g, IB analysis of WCLs and anti-Flag IPs derived from WDR24 KO HEK 293 cells reconstituted with indicated constructs. The cells were deprived of glucose for 60 min and restimulated with glucose for 10 min as indicated. h, IB analysis of WCLs and IPs derived from HEK 293 cells transfected with indicated plasmids. i, IB analysis of WCLs and anti-WDR24 IPs derived from WT and 14-3-3γ knockdown HEK 293 cells. The cells were treated as (f,g). j, IB analysis of WCLs and anti-Flag IPs derived from WDR24 KO HEK 293 cells reconstituted with indicated constructs. k,l, Wild-type (WT) and Sesn1/2/3 knockout MEFs were deprived of amino acids (AA) (k) or glucose (Glc) (l) for 60 min and restimulated with amino acids for 10 min as indicated. WCLs were analyzed via IB. Representative image shown, a-j and i, n = 2; k, n = 3.
Extended Data Fig. 8 Generation of Wdr24S155D and Wdr24S155A knock-in mice by CRISPR-Cas9-mediated genome editing.
a, sgRNA sequence and part of ssODN sequence used for generating Wdr24S155A/D knock-in mice. b, Sanger sequencing results of hetero Wdr24S155D knock-in mouse genomic DNA. c, Sanger sequencing results of hetero Wdr24S155A knock-in mouse genomic DNA. d, Neonates from WDR24+/A parents were counted at birth.
Extended Data Fig. 9 Phospho-deficient Wdr24S155A knock-in mice show relatively high mTORC1 activity under fasting.
a, Representative images of hematoxylin and eosin (H&E) (scale bar, 50 μm), p-S6(S40/244) (scale bar, 100 μm) staining of the heart section (n = 3) of Wdr24+/+and Wdr24A/A littermates. The mice were fasted for 24 h, or fasted and refed for 2 h. b, IB analysis of WCLs derived from Wdr24+/+or Wdr24A/A mouse livers. The mice were fasted for 24 h, or fasted and refed for 2 h. n = 3 mice. c, Representative images of hematoxylin and eosin (H&E) (scale bar, 50 μm), p-S6(S240/244) staining (scale bar, 100 μm; insets magnification=1.5) of the kidney section (n = 3) of Wdr24+/+and Wdr24A/A littermates. The mice were fasted for 24 h, or fasted and refed for 2 h. d, IB analysis of WCLs derived from Wdr24+/+or Wdr24A/A mouse kidneys. The mice were fasted for 24 h or fasted and refed for 2 h. n = 3 mice. e,f, IF analysis of the kidney section of Wdr24+/+and Wdr24A/A littermates (e). Scale bar, 20 μm. The mice were fasted for 24 h, or fasted and refed for 2 h. The pS6 (240/244) intensity was quantified via Image J (f). n = 7, 6, 6, 6. P = 1.27E-06, 5.95E-07, 0.01. Data are mean ± s.d., two-tailed t-test. *P < 0.05, ***P < 0.001.
Extended Data Fig. 10 The WDR24-S155A mutation partially regulates mTORC1 lysosome localization under glucose starvation.
a, IB analysis of WCLs derived from Wdr24+/+or Wdr24A/A MEFs. The cells were deprived of amino acids for 60 min and restimulated with amino acids for 10 min as indicated. Representative image shown, n = 2. b, IF analysis of Wdr24+/+or Wdr24A/A MEFs. Indicated cells were deprived of glucose for 60 min and restimulated with glucose for 10 min as indicated. Scale bar, 10 μm. c, The imaging data in (b) were quantified. n = 14, 12, 12, 14. P = 4.74E-09, 1.57E-08, 0.003. Data are the mean ± s.d., two-tailed t-test. **P < 0.01, ***P < 0.001. d, IF analysis of Wdr24+/+or Wdr24A/A MEFs. Indicated cells were deprived of amino acids for 60 min and restimulated with amino acids for 10 min as indicated. Scale bar, 10 μm. e, The imaging data in (d) were quantified. n = 15, 14, 11, 13. P = 1.05E-07, 0.08, 1.72E-07. Data are the mean ± s.d., two-tailed t-test. NS, not significant. ***P < 0.001. f, A working model to show how glucose regulates mTORC1 kinase activity through AMPK-mediated WDR24, Raptor and TSC2 phosphorylation.
Supplementary information
Supplementary Tables 1–3
Supplementary Table 1: Information about antibodies. Supplementary Table 2: List of primers, sgRNAs and ssODNs. Supplementary Table 3: Quantification of western blots in the figures.
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Dai, X., Jiang, C., Jiang, Q. et al. AMPK-dependent phosphorylation of the GATOR2 component WDR24 suppresses glucose-mediated mTORC1 activation. Nat Metab 5, 265–276 (2023). https://doi.org/10.1038/s42255-022-00732-4
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DOI: https://doi.org/10.1038/s42255-022-00732-4
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