Mechanisms underlying inflammation in mevalonate kinase deficiency

Mevalonate kinase deficiency is an autoinflammatory metabolic disorder caused by biallelic pathogenic variants in the MVK gene characterized by lifelong recurring and often unprovoked episodes of inflammation. Mevalonate kinase is an early enzyme of the isoprenoid biosynthesis pathway, which supplies cells with both non-sterol and sterol isoprenoids, such as geranylgeranyl-PP and cholesterol, which are essential for numerous cellular processes. The resulting temperature-sensitive decreased mevalonate kinase activity makes the flux through the pathway vulnerable to disturbances, including elevated temperatures during fever and stress, which trigger the inflammatory episodes. The autoinflammatory symptoms, including elevated cytokines, associated with mevalonate kinase deficiency point to a role for isoprenoids in the regulation of the innate immune response.
This thesis reports the identification of several cellular processes and signaling pathways affected by mevalonate kinase deficiency in different cellular models, including patient-derived cells and CRISPR-CAS9-edited monocytic THP-1 cells. The finding that supplementing cells with isoprenoid precursors or directing the pathway flux towards geranylgeranyl-PP synthesis using specific enzyme inhibitors corrected the cellular defects confirms that manipulating the isoprenoid biosynthesis pathway may offer possible therapies for mevalonate kinase deficiency. Screening a small compound library with reporter cells identified multiple compounds that increased mevalonate kinase levels and isoprenoid biosynthesis in patient fibroblasts. Taken together, the enhanced understanding of the molecular pathways and cellular processes affected by mevalonate kinase deficiency has improved the understanding of its pathogenesis and contributes to the identification of new potential therapeutic targets.