Mevalonate kinase deficiency (MKD) is an autoinflammatory disease caused by systemic  inflammation inducing multi-organ dysfunction. High levels of the inflammatory cytokine IL-1ß is the main cause of the MKD-induced inflammatory phenotype, however the molecular mechanisms responsible for IL-1ß production are still unclear. Previous research has demonstrated that inhibition of prenylation by deficiency in the prenylation enzyme geranylgeranyltransferase-I (GGTase-I) can cause high IL-1ß production and the development of joint inflammation as seen in patients with MKD. More than 100 proteins, including RHO family proteins, need to be prenylated for their function and activity, however, the critical unprenylated substrate responsible for inflammatory reactions in GGTase-I deficient mice is not known. Interestingly, treatment with statins was shown to mimic effects of GGTase-I deficiency by inducing high IL-1ß production in macrophages via hyperactivation of RHO family proteins. This project aims to identify and validate the critical unlipidated substrate(s) responsible for the development of the inflammatory phenotype in GGTase-I knockout mice, and to shed light on the detrimental effects of long-term statin use. For this, we will use state-of-art technologies including CRISPR-Cas9 genetic screens and genetic targeting in mice in order to identify the molecular mechanisms responsible for the inflammation induced by unlipidated proteins.