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It is currently believed that the inflammatory phenotype of MKD is triggered by temperature\u2010sensitive 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<jats:italic>in vitro<\/jats:italic>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\u2009\u00b0C compared with 37\u2009\u00b0C. This included a 200% increase in unprenylated Rab7A, Rab14 and Rab1A. Inhibition of sterol regulatory element\u2010binding 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\u2010mediated upregulation of enzymes required for isoprenoid biosynthesis. Furthermore, while inhibition of Rho\/Rac\/Rap prenylation promoted the release of IL\u20101\u03b2, specific inhibition of Rab prenylation by NE10790 had no effect in human peripheral blood mononuclear cells or human THP\u20101 monocytic cells. These studies demonstrate for the first time that mutations in mevalonate kinase can lead to a mild, temperature\u2010induced defect in the prenylation of small GTPases, but that loss of prenylated Rab GTPases is not the cause of enhanced IL\u20101\u03b2 release in MKD.<\/jats:p>","DOI":"10.1038\/icb.2016.58","type":"journal-article","created":{"date-parts":[[2016,7,5]],"date-time":"2016-07-05T09:52:14Z","timestamp":1467712334000},"page":"994-999","source":"Crossref","is-referenced-by-count":43,"title":["Mevalonate kinase deficiency leads to decreased prenylation of Rab GTPases"],"prefix":"10.1111","volume":"94","author":[{"given":"Julie","family":"Jurczyluk","sequence":"first","affiliation":[{"name":"Garvan Institute of Medical Research and St Vincent's Clinical School, UNSW Australia Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcia A","family":"Munoz","sequence":"additional","affiliation":[{"name":"Garvan Institute of Medical Research and St Vincent's Clinical School, UNSW Australia Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oliver P","family":"Skinner","sequence":"additional","affiliation":[{"name":"Garvan Institute of Medical Research and St Vincent's Clinical School, UNSW Australia Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan C","family":"Chai","sequence":"additional","affiliation":[{"name":"Garvan Institute of Medical Research and St Vincent's Clinical School, UNSW Australia Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naveid","family":"Ali","sequence":"additional","affiliation":[{"name":"Garvan Institute of Medical Research and St Vincent's Clinical School, UNSW Australia Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Umaimainthan","family":"Palendira","sequence":"additional","affiliation":[{"name":"Garvan Institute of Medical Research and St Vincent's Clinical School, UNSW Australia Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julian MW","family":"Quinn","sequence":"additional","affiliation":[{"name":"Garvan Institute of Medical Research and St Vincent's Clinical School, UNSW Australia Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra","family":"Preston","sequence":"additional","affiliation":[{"name":"Garvan Institute of Medical Research and St Vincent's Clinical School, UNSW Australia Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stuart G","family":"Tangye","sequence":"additional","affiliation":[{"name":"Garvan Institute of Medical Research and St Vincent's Clinical School, UNSW Australia Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew J","family":"Brown","sequence":"additional","affiliation":[{"name":"School of Biotechnology &amp; 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