Glucose-oxygen deprivation constrains HMGCR function and Rac1 prenylation and activates the NLRP3 inflammasome in human monocytes

IF 6.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Nora Raulien, Kathleen Friedrich, Sarah Strobel, Stefanie Raps, Friederike Hecker, Matthias Pierer, Erik Schilling, Elke Lainka, Tilmann Kallinich, Sven Baumann, Katarina Fritz-Wallace, Ulrike Rolle-Kampczyk, Martin von Bergen, Achim Aigner, Alexander Ewe, Georg Schett, Michael Cross, Manuela Rossol, Ulf Wagner
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引用次数: 0

Abstract

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.
葡萄糖-氧气剥夺限制了人类单核细胞中 HMGCR 的功能和 Rac1 的前酰化,并激活了 NLRP3 炎症小体。
缺氧和低葡萄糖常常同时出现在炎症部位。在单核细胞和巨噬细胞中,葡萄糖-氧气匮乏会刺激 NLRP3 炎性体的组装,从而产生促炎细胞因子 IL-1β。我们发现,同时缺糖和缺氧会限制甲羟戊酸激酶途径的限速酶 HMG-CoA 还原酶(HMGCR)的功能,从而激活 NLRP3 炎症小体。HMGCR 参与了香叶基纯丙基焦磷酸(GGPP)的合成,而 GGPP 是蛋白质的前酰化和脂膜整合所必需的。在葡萄糖-氧气匮乏条件下,GGPP合成减少,导致小GTP酶Rac1的前酰化减少,非前酰化的Rac1与支架蛋白IQGAP1的结合增加,NLRP3炎性体的活化增强。在氧气和葡萄糖供应受限的情况下,因甲羟戊酸激酶缺乏症或 Muckle-Wells 综合征而导致甲羟戊酸途径受损的患者单核细胞比对照组单核细胞释放出更多的 IL-1β。因此,在葡萄糖-氧气匮乏条件下,由于抑制 HMGCR 而减少了 GGPP 的合成,导致了先天性促炎反应,而 Rac1 的前酰化通常会抑制这种反应。我们认为,这种机制在炎症性自身免疫疾病中也很活跃。
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来源期刊
Science Signaling
Science Signaling BIOCHEMISTRY & MOLECULAR BIOLOGY-CELL BIOLOGY
CiteScore
9.50
自引率
0.00%
发文量
148
审稿时长
3-8 weeks
期刊介绍: "Science Signaling" is a reputable, peer-reviewed journal dedicated to the exploration of cell communication mechanisms, offering a comprehensive view of the intricate processes that govern cellular regulation. This journal, published weekly online by the American Association for the Advancement of Science (AAAS), is a go-to resource for the latest research in cell signaling and its various facets. The journal's scope encompasses a broad range of topics, including the study of signaling networks, synthetic biology, systems biology, and the application of these findings in drug discovery. It also delves into the computational and modeling aspects of regulatory pathways, providing insights into how cells communicate and respond to their environment. In addition to publishing full-length articles that report on groundbreaking research, "Science Signaling" also features reviews that synthesize current knowledge in the field, focus articles that highlight specific areas of interest, and editor-written highlights that draw attention to particularly significant studies. This mix of content ensures that the journal serves as a valuable resource for both researchers and professionals looking to stay abreast of the latest advancements in cell communication science.
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