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The Warburg effect controls cell growth and differentiation by altering N-glycosylation

  • Author(s): Araujo, Lindsey Renee
  • Advisor(s): Demetriou, Michael
  • et al.

Rapidly proliferating cells such as T cells undergo the Warburg effect [1-3], a long-standing and poorly understood phenomenon that increases glucose uptake yet paradoxically reduces energy from glucose via a switch from oxidative phosphorylation to aerobic glycolysis. This has been rationalized as increased requirements for glucose-derived metabolites in biomass generation and/or limiting oxidative stress [4-7]. Asn (N)-linked protein glycosylation requires glucose and multiple glucose-derived sugars [8], yet surprisingly this pathway has not been investigated as a target of the Warburg effect. Here we report that the Warburg effect drives T cell growth and differentiation by controlling glucose flux to Golgi N-glycosylation. Branched N-glycans regulate the concentration and signaling of multiple surface receptors and transporters simultaneously to coordinate cellular and disease phenotypes [8-20]. Branching depends on UDP-GlcNAc biosynthesis via the hexosamine pathway [10, 11, 21, 22], a competitor of glycolysis for fructose-6-phosphate. In glycolytic T cells, the hexosamine pathway is starved of fructose-6-phosphate by glycolysis, limiting de novo UDP-GlcNAc biosynthesis and N-glycan branching dependent IL-2 receptor-α (CD25) surface retention. Restoring branching or UDP-GlcNAc levels via salvage of N-acetylglucosamine does not alter the glycolytic state yet inhibits T cell growth and switches cell fate from pro-inflammatory TH17 to anti-inflammatory induced T regulatory (iTreg) cells by restoring CD25 surface expression. Forcing oxidative phosphorylation inhibits growth and drives iTreg over TH17 differentiation by raising branching, demonstrating that glycolysis is not required for growth/differentiation control beyond its regulation of branching. Thus, the Warburg effect primarily targets N-glycosylation via altered glucose flux to control T cell growth and differentiation.

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