Yersinia infection induces glucose depletion and AMPK-dependent inhibition of pyroptosis in mice

Nat Microbiol. 2024 Aug;9(8):2144-2159. doi: 10.1038/s41564-024-01734-6. Epub 2024 Jun 6.

Abstract

Nutritional status and pyroptosis are important for host defence against infections. However, the molecular link that integrates nutrient sensing into pyroptosis during microbial infection is unclear. Here, using metabolic profiling, we found that Yersinia pseudotuberculosis infection results in a significant decrease in intracellular glucose levels in macrophages. This leads to activation of the glucose and energy sensor AMPK, which phosphorylates the essential kinase RIPK1 at S321 during caspase-8-mediated pyroptosis. This phosphorylation inhibits RIPK1 activation and thereby restrains pyroptosis. Boosting the AMPK-RIPK1 cascade by glucose deprivation, AMPK agonists, or RIPK1-S321E knockin suppresses pyroptosis, leading to increased susceptibility to Y. pseudotuberculosis infection in mice. Ablation of AMPK in macrophages or glucose supplementation in mice is protective against infection. Thus, we reveal a molecular link between glucose sensing and pyroptosis, and unveil a mechanism by which Y. pseudotuberculosis reduces glucose levels to impact host AMPK activation and limit host pyroptosis to facilitate infection.

MeSH terms

  • AMP-Activated Protein Kinases* / metabolism
  • Animals
  • Glucose* / metabolism
  • Macrophages* / metabolism
  • Macrophages* / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Pyroptosis*
  • Receptor-Interacting Protein Serine-Threonine Kinases* / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases* / metabolism
  • Yersinia pseudotuberculosis Infections / metabolism
  • Yersinia pseudotuberculosis Infections / microbiology
  • Yersinia pseudotuberculosis* / metabolism
  • Yersinia pseudotuberculosis* / pathogenicity

Substances

  • AMP-Activated Protein Kinases
  • Glucose
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse