title: Unprenylated RhoA contributes to IL-1β hypersecretion in mevalonate kinase deficiency model through stimulation of Rac1 activity.
abstract: 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-1β 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 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 toward interleukin 1β production and elucidate the effects of protein prenylation in monocytes.
authors.affiliation: From Department of Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht, Wilhelmina Children's Hospital, 3584 EA, Utrecht, the Netherlands and.
authors.forename: Robert
authors.initials: R
authors.lastname: van der Burgh
authors.affiliation: From Department of Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht, Wilhelmina Children's Hospital, 3584 EA, Utrecht, the Netherlands and.
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Pervolaraki
authors.affiliation: Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam Medical Center, University of Amsterdam, 1100 DE, Amsterdam, the Netherlands.
authors.forename: Marjolein
authors.initials: M
authors.lastname: Turkenburg
authors.affiliation: Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam Medical Center, University of Amsterdam, 1100 DE, Amsterdam, the Netherlands.
authors.forename: Hans R
authors.initials: HR
authors.lastname: Waterham
authors.affiliation: From Department of Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht, Wilhelmina Children's Hospital, 3584 EA, Utrecht, the Netherlands and.
authors.forename: Joost
authors.initials: J
authors.lastname: Frenkel
authors.affiliation: From Department of Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht, Wilhelmina Children's Hospital, 3584 EA, Utrecht, the Netherlands and mboes@umcutrecht.nl.
authors.forename: Marianne
authors.initials: M
authors.lastname: Boes
mesh_terms: D002460:Cell Line; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D054078:Mevalonate Kinase Deficiency / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D017368:Protein Prenylation; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; C107953:RAC1 protein, human; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein
keywords: Autoinflammatory-disorder; Autophagy; Interleukin; Mitochondrial Elongation; Protein Isoprenylation; Ras Homolog Gene Family, Member A (RhoA); Ras-related C3 Botulinum Toxin Substrate 1 (Rac1); Small GTPase
references.citation: Nat Rev Mol Cell Biol. 2008 Nov;9(11):846-59
references.pmid: 18946474
references.citation: Immunol Rev. 2011 Sep;243(1):136-51
references.pmid: 21884173
references.citation: Nat Genet. 1999 Jun;22(2):175-7
references.pmid: 10369261
references.citation: Infect Immun. 2001 Dec;69(12):7535-43
references.pmid: 11705930
references.citation: Sci Signal. 2013 Dec 17;6(306):ra108
references.pmid: 24345679
references.citation: Nat Genet. 1999 Jun;22(2):178-81
references.pmid: 10369262
references.citation: Cell Mol Life Sci. 2011 Oct;68(20):3349-58
references.pmid: 21687989
references.citation: Int J Biochem Cell Biol. 2013 Mar;45(3):745-52
references.pmid: 23147595
references.citation: Autophagy. 2008 Oct;4(7):849-50
references.pmid: 18758232
references.citation: Science. 1999 Mar 26;283(5410):2083-5
references.pmid: 10092231
references.citation: Endocrinology. 2010 Sep;151(9):4313-23
references.pmid: 20591975
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):904-9
references.pmid: 12538863
references.citation: J Biol Chem. 2001 Nov 2;276(44):40977-81
references.pmid: 11533055
references.citation: J Biol Chem. 2014 Feb 21;289(8):5000-12
references.pmid: 24356959
references.citation: Blood. 2008 Nov 1;112(9):3563-73
references.pmid: 18684863
references.citation: Arthritis Rheum. 2006 Nov;54(11):3690-5
references.pmid: 17075828
references.citation: J Biol Chem. 1996 Jun 7;271(23):13556-60
references.pmid: 8662891
references.citation: Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3000-4
references.pmid: 1557405
references.citation: Annu Rev Biochem. 1999;68:459-86
references.pmid: 10872457
references.citation: Eur J Cancer. 2000 Jun;36(10):1269-74
references.pmid: 10882865
references.citation: J Cell Biol. 2008 May 5;181(3):485-96
references.pmid: 18443222
references.citation: J Biol Chem. 2007 Aug 31;282(35):25464-74
references.pmid: 17595159
references.citation: Cell. 2000 Feb 4;100(3):345-56
references.pmid: 10676816
references.citation: J Biol Chem. 2007 Mar 16;282(11):8069-78
references.pmid: 17234627
references.citation: Annu Rev Cell Dev Biol. 2005;21:247-69
references.pmid: 16212495
references.citation: Int J Cancer. 2011 Jul 1;129(1):61-9
references.pmid: 20824700
references.citation: J Cell Biol. 1998 Nov 30;143(5):1385-98
references.pmid: 9832565
references.citation: J Biol Chem. 1992 Apr 25;267(12):7983-6
references.pmid: 1569056
references.citation: Mol Immunol. 2008 Apr;45(8):2158-65
references.pmid: 18242710
references.citation: Ann Med. 2003;35(6):398-403
references.pmid: 14572163
references.citation: Life Sci. 2004 Jul 30;75(11):1333-41
references.pmid: 15234191
references.citation: J Inherit Metab Dis. 2010 Oct;33(5):625-32
references.pmid: 20814828
references.citation: J Biol Chem. 2000 Dec 22;275(51):40073-81
references.pmid: 11007780
references.citation: J Biol Chem. 2003 Feb 21;278(8):5736-43
references.pmid: 12477733
references.citation: J Cell Biol. 1999 Nov 29;147(5):1009-22
references.pmid: 10579721
references.citation: Annu Rev Cell Dev Biol. 2006;22:79-99
references.pmid: 16704336
references.citation: Biochem Pharmacol. 2008 Jan 15;75(2):405-13
references.pmid: 17920041
references.citation: Biochem J. 2005 Aug 15;390(Pt 1):1-9
references.pmid: 16083425