Mevalonate kinase deficiency leads to decreased prenylation of Rab GTPases

Abstract

Mevalonate kinase deficiency (MKD) is caused by mutations in a key enzyme of the mevalonate–cholesterol biosynthesis pathway, leading to recurrent autoinflammatory disease characterised by enhanced release of interleukin-1β (IL-1β). It is currently believed that the inflammatory phenotype of MKD is triggered by temperature-sensitive loss of mevalonate kinase activity and reduced biosynthesis of isoprenoid lipids required for the prenylation of small GTPase proteins. However, previous studies have not clearly shown any change in protein prenylation in patient cells under normal conditions. With lymphoblast cell lines from two compound heterozygous MKD patients, we used a highly sensitive in vitro prenylation assay, together with quantitative mass spectrometry, to reveal a subtle accumulation of unprenylated Rab GTPases in cells cultured for 3 days or more at 40 °C compared with 37 °C. This included a 200% increase in unprenylated Rab7A, Rab14 and Rab1A. Inhibition of sterol regulatory element-binding protein (SREBP) activation by fatostatin led to more pronounced accumulation of unprenylated Rab proteins in MKD cells but not parent cells, suggesting that cultured MKD cells may partially overcome the loss of isoprenoid lipids by SREBP-mediated upregulation of enzymes required for isoprenoid biosynthesis. Furthermore, while inhibition of Rho/Rac/Rap prenylation promoted the release of IL-1β, specific inhibition of Rab prenylation by NE10790 had no effect in human peripheral blood mononuclear cells or human THP-1 monocytic cells. These studies demonstrate for the first time that mutations in mevalonate kinase can lead to a mild, temperature-induced defect in the prenylation of small GTPases, but that loss of prenylated Rab GTPases is not the cause of enhanced IL-1β release in MKD.

Lack of Prenylated Proteins, Autophagy Impairment and Apoptosis in SH-SY5Y Neuronal Cell Model of Mevalonate Kinase Deficiency

“…A recent study indicates that the Rab family of GTPase is not involved into release of IL-1β from MKD patients monocytes after an high temperature stimulus [38]. Rab GTPases necessitate of geranylgeranyl post-translational modification to be attached to membranes and then activated; thus these results further confirm our findings on the important role of farnesylation and not only geranylgeranylation in MKD pathogenesis.…”

The Mevalonate Pathway Is a Druggable Target for Vaccine Adjuvant Discovery

“…Moreover, co-administration of simvastatin with GGPP restored the normal cellular distribution of Rab5 ( Figure 5D). These results are consistent with the observation that mevalonate kinase deficiency leads to decreased prenylation of Rab GTPase (Jurczyluk et al, 2016). We thus propose that simvastatin functions by inhibiting the formation of GGPP that is required for geranylgeranylation of small GTPases (including Rab5) in APCs, resulting in arrested endosomal maturation, prolonged antigen retention, increased antigen presentation, and T cell activation.…”

Mevalonate kinase deficiency: therapeutic targets, treatments, and outcomes

“…Furthermore, isoprenoids and sterols derived from mevalonate can also play a direct role in DNA transcription, enzymatic regulation and response to oxidative stress [46][47][48].…”