Unprenylated RhoA contributes to IL-1{beta} hypersecretion in mevalonate kinase deficiency model through stimulation of Rac1 activity [Molecular Bases of Disease]

August 8th, 2014 by van der Burgh, R., Pervolaraki, K., Turkenburg, M., Waterham, H. R., Frenkel, J., Boes, M.

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 affected are small GTPases, including Rac1 and RhoA. It had not been understood how protein prenylation of small GTPases relates to GTP hydrolysis activity and downstream signaling. We here investigated the contribution of RhoA prenylation to the biochemical pathways that underlie MKD-associated IL-1β hyper secretion, 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 1β 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 towards interleukin 1β production, and elucidate the effects of protein prenylation in monocytes.
  • Posted in Journal of Biological Chemistry, Publications
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