TY - JOUR A1 - Raulien, Nora A1 - Friedrich, Kathleen A1 - Strobel, Sarah A1 - Raps, Stefanie A1 - Hecker, Friederike A1 - Pierer, Matthias A1 - Schilling, Erik A1 - Lainka, Elke A1 - Kallinich, Tilmann A1 - Baumann, Sven A1 - Fritz-Wallace, Katarina A1 - Rolle-Kampczyk, Ulrike A1 - Bergen, Martin von A1 - Aigner, Achim A1 - Ewe, Alexander A1 - Schett, Georg A1 - Cross, Michael A1 - Rossol, Manuela A1 - Wagner, Ulf T1 - Glucose-oxygen deprivation constrains HMGCR function and Rac1 prenylation and activates the NLRP3 inflammasome in human monocytes JF - Science Signaling N2 - Hypoxia and low glucose abundance often occur simultaneously at sites of inflammation. In monocytes and macrophages, glucose-oxygen deprivation stimulates the assembly of the NLRP3 inflammasome to generate the proinflammatory cytokine IL-1β. We found that concomitant glucose deprivation and hypoxia activated the NLRP3 inflammasome by constraining the function of HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate kinase pathway. HMGCR is involved in the synthesis of geranylgeranyl pyrophosphate (GGPP), which is required for the prenylation and lipid membrane integration of proteins. Under glucose-oxygen deprivation, GGPP synthesis was decreased, leading to reduced prenylation of the small GTPase Rac1, increased binding of nonprenylated Rac1 to the scaffolding protein IQGAP1, and enhanced activation of the NLRP3 inflammasome. In response to restricted oxygen and glucose supply, patient monocytes with a compromised mevalonate pathway due to mevalonate kinase deficiency or Muckle-Wells syndrome released more IL-1β than did control monocytes. Thus, reduced GGPP synthesis due to inhibition of HMGCR under glucose-oxygen deprivation results in proinflammatory innate responses, which are normally kept in check by the prenylation of Rac1. We suggest that this mechanism is also active in inflammatory autoimmune conditions. Y1 - 2024 U6 - https://doi.org/10.1126/scisignal.add8913 SN - 1945-0877 VL - 17 IS - 845 PB - American Association for the Advancement of Science (AAAS) ER -