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.

营养状况和细胞焦亡对于宿主防御感染很重要。然而，微生物感染期间将营养感应整合到焦亡中的分子联系尚不清楚。在这里，通过代谢分析，我们发现假结核耶尔森菌感染导致巨噬细胞的细胞内葡萄糖水平显着降低。这会导致葡萄糖和能量传感器 AMPK 的激活，从而在 caspase-8 介导的焦亡过程中磷酸化 S321 处的必需激酶 RIPK1。这种磷酸化抑制 RIPK1 激活，从而抑制细胞焦亡。通过葡萄糖剥夺、AMPK 激动剂或 RIPK1-S321E 敲入增强 AMPK-RIPK1 级联可抑制焦亡，导致小鼠对假结核杆菌感染的易感性增加。消除小鼠巨噬细胞中的 AMPK 或补充葡萄糖可预防感染。因此，我们揭示了葡萄糖传感和焦亡之间的分子联系，并揭示了假结核杆菌降低葡萄糖水平以影响宿主 AMPK 激活并限制宿主焦亡以促进感染的机制。