The role of mevalonate pathway metabolites in immune homeostasis 2308615

Abstract Introduction The mevalonate pathway is a crucial metabolic pathway responsible for synthesizing key intermediates, including steroids and non-steroidal isoprenoids. Isoprenoid metabolites such as geranylgeranyl pyrophosphate (GGPP) are essential for protein prenylation, a post-translational modification that regulates the localization and function of numerous signaling and structural proteins. The importance of this pathway in immune homeostasis is underscored by the fact that rare inborn errors in enzymes of the pathway such as mevalonate kinase deficiency (MKD), are linked to a spectrum of autoinflammatory syndromes. Mild form of MKD results in hyper-IgD syndrome (HIDS), characterized by recurrent fever episodes, joint pain, abdominal pain, and lymphadenopathy. Current treatments for HIDS are primarily symptomatic and do not target the underlying metabolic deficiency. Methods To gain deeper insights into the immunometabolic crosstalk in HIDS, we conducted a comprehensive metabolomic and proteomic analysis of patient plasma. Additionally, to investigate the therapeutic potential of isoprenoid supplementation, we conducted a pilot study assessing the impact of geranylgeraniol, a GGPP surrogate, on inflammatory status of HIDS patients. Results The analysis identified disease-specific proteomic and metabolic plasma signatures and revealed processes dysregulated by mevalonate pathway dysfunction, including isoprenoids and other lipid species in the plasma of HIDS patients. Geranylgeraniol supplementation impacted global protein and metabolic signatures, confirmed by targeted measurements of inflammatory markers, suggesting potential therapeutic benefit and warranting further study. Conclusion In summary, our study deepens the understanding of the metabolic-immune interface in the context of mevalonate pathway dysfunctions and isoprenoid deficiency and suggests that targeting isoprenoid deficiency may offer a strategy to modulate disease-specific changes and inflammation in HIDS. Funding Source 1) Washington University Institute of Clinical and Transitional Sciences; 2) Longer Life Foundation Topic Categories Immune Mechanisms of Human Disease (HUM)