AMPK-dependent phosphorylation of the GATOR2 component WDR24 suppresses glucose-mediated mTORC1 activation

  • Nat Metab. 2023 Feb;5(2):265-276. doi: 10.1038/s42255-022-00732-4.
Xiaoming Dai  #  1 ,  Cong Jiang  #  1 ,  Qiwei Jiang  #  2 ,  Lan Fang  3 ,  Haihong Yu  3 ,  Jinhe Guo  2 ,  Peiqiang Yan  1 ,  Fangtao Chi  4 ,  Tao Zhang  1 ,  Hiroyuki Inuzuka  1 ,  John M Asara  5 ,  Ping Wang  3 ,  Jianping Guo  6 ,  Wenyi Wei  7
Affiliations
  • 1. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • 2. Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 3. Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, School of Life Sciences and Technology, Tongji University, Shanghai, China.
  • 4. The David H. Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 5. Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • 6. Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 7. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. [email protected].
  • # Contributed equally.
PMID: 36732624 DOI: 10.1038/s42255-022-00732-4
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.