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<p>Cell survival requires tight coordination between growth-promoting metabolism and cellular quality-control pathways, yet how these processes are integrated remains unclear. Here we identify the conserved glycolytic enzyme PGAM1 as a metabolic-autophagy checkpoint that links glycolysis to autophagy initiation independently of its catalytic activity. Using complementary yeast and mammalian systems we show that PGAM1 functions as a molecular scaffold that recruits phosphatidylinositol 3-kinase complex I to the phagophore assembly site, thereby licensing autophagosome biogenesis. This autophagy-regulatory function is genetically essential, evolutionarily conserved and functionally separable from glycolysis. It is regulated by Atg1/ULK1-mediated phosphorylation that enhances Atg14 binding under starvation. Functionally, PGAM1 coordinates anabolic growth and stress-induced survival to maintain cellular homeostasis. In cancer, PGAM1 upregulation enhances both glycolytic flux and autophagy capacity. Disruption of either function markedly impairs tumour growth, establishing PGAM1 as a homeostatic checkpoint that is hijacked in cancer to drive both proliferation and stress tolerance.</p>

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The glycolytic enzyme PGAM1 functions as a metabolic–autophagy checkpoint to coordinate growth and stress tolerance

  • 期刊论文

  • 发表日期：

    2026年7月29日

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  • Yi Zhang,
  • Pengwei Zhao,
  • Hangfei Liang,
  • Zhaojie Liu,
  • Shuling Dong,
  • Yingcong Chen,
  • Weijing Yao,
  • Yuting Chen,
  • Liting Yang,
  • Zhonglan Shi,
  • Lei Zhang,
  • Yibin Pan,
  • Fanghong Zheng,
  • Qi Lin,
  • Shichao Wang,
  • Jinheng Pan,
  • Mingzhu Fan,
  • Shan Feng,
  • Cheng Ma,
  • Lifeng Pan,
  • Ying Xing,
  • Fan Yang,
  • Shuiping Liu,
  • Du Feng,
  • Qiming Sun,
  • Guixin Zhu,
  • Cong Yi

摘要

Cell survival requires tight coordination between growth-promoting metabolism and cellular quality-control pathways, yet how these processes are integrated remains unclear. Here we identify the conserved glycolytic enzyme PGAM1 as a metabolic-autophagy checkpoint that links glycolysis to autophagy initiation independently of its catalytic activity. Using complementary yeast and mammalian systems we show that PGAM1 functions as a molecular scaffold that recruits phosphatidylinositol 3-kinase complex I to the phagophore assembly site, thereby licensing autophagosome biogenesis. This autophagy-regulatory function is genetically essential, evolutionarily conserved and functionally separable from glycolysis. It is regulated by Atg1/ULK1-mediated phosphorylation that enhances Atg14 binding under starvation. Functionally, PGAM1 coordinates anabolic growth and stress-induced survival to maintain cellular homeostasis. In cancer, PGAM1 upregulation enhances both glycolytic flux and autophagy capacity. Disruption of either function markedly impairs tumour growth, establishing PGAM1 as a homeostatic checkpoint that is hijacked in cancer to drive both proliferation and stress tolerance.