Unprenylated RhoA Contributes to IL-1 beta Hypersecretion in Mevalonate Kinase Deficiency Model through Stimulation of Rac1 Activity

Background: Shortage of isoprenoids causes aberrant activity of prenylated small GTPases. Results: Inactivation of RhoA due to lack of prenylation leads to Rac1 activation and subsequent priming for IL-1 secretion. Conclusion: RhoA inactivation contributes to the pathology of isoprenoid deficiency. Significance: Insight into the multiple networks involving RhoA will benefit new intervention strategies in prenylation-related pathologies.

Protein prenylation is a post-translational modification whereby non-sterol isoprenoid lipid chains are added, thereby modifying the molecular partners with which proteins interact. The autoinflammatory disease mevalonate kinase deficiency (MKD) is characterized by a severe reduction in protein prenylation. A major class of proteins that are affected are small GTPases, including Rac1 and RhoA. It is not clear how protein prenylation of small GTPases relates to GTP hydrolysis activity and downstream signaling. Here, we investigated the contribution of RhoA prenylation to the biochemical pathways that underlie MKD-associated IL-1 hypersecretion using human cell cultures, Rac1 and RhoA protein variants, and pharmacological inhibitors. We found that when unprenylated, the GTP-bound levels of RhoA decrease, causing a reduction in GTPase activity and increased protein kinase B (PKB) phosphorylation. Cells expressing unprenylated RhoA produce increased levels of interleukin 1 mRNA. Of other phenotypic cellular changes seen in MKD, increased mitochondrial potential and mitochondrial elongation, only mitochondrial elongation was observed. Finally, we show that pharmacological inactivation of RhoA boosts Rac1 activity, a small GTPase whose activity was earlier implied in MKD pathogenesis. Together, our data show that RhoA plays a pivotal role in MKD pathogenesis through Rac1/PKB signaling toward interleukin 1 production and elucidate the effects of protein prenylation in monocytes.