title: Dimethyl fumarate blocks pro-inflammatory cytokine production via inhibition of TLR induced M1 and K63 ubiquitin chain formation.
abstract: Dimethyl fumarate (DMF) possesses anti-inflammatory properties and is approved for the treatment of psoriasis and multiple sclerosis. While clinically effective, its molecular target has remained elusive - although it is known to activate anti-oxidant pathways. We find that DMF inhibits pro-inflammatory cytokine production in response to TLR agonists independently of the Nrf2-Keap1 anti-oxidant pathway. Instead we show that DMF can inhibit the E2 conjugating enzymes involved in K63 and M1 polyubiquitin chain formation both in vitro and in cells. The formation of K63 and M1 chains is required to link TLR activation to downstream signaling, and consistent with the block in K63 and/or M1 chain formation, DMF inhibits NFκB and ERK1/2 activation, resulting in a loss of pro-inflammatory cytokine production. Together these results reveal a new molecular target for DMF and show that a clinically approved drug inhibits M1 and K63 chain formation in TLR induced signaling complexes. Selective targeting of E2s may therefore be a viable strategy for autoimmunity.
authors: Division of Cell Signaling and Immunology, School of Life Sciences, Wellcome Trust Building, University of Dundee, Dow St, Dundee, DD1 5EH, UK.
authors: Victoria A
authors: VA
authors: McGuire
authors: Division of Cell Signaling and Immunology, School of Life Sciences, Wellcome Trust Building, University of Dundee, Dow St, Dundee, DD1 5EH, UK.|Department of Chemistry and Biochemistry, Faculty of Pharmacy, CEU San Pablo University, Urbanización Montepríncipe, 28668 Madrid, Spain.
authors: Tamara
authors: T
authors: Ruiz-Zorrilla Diez
authors: MRC Protein Phosphorylation and ubiquitylation Unit, School of Life Sciences, Sir James Black Centre, University of Dundee, Dow St, Dundee, DD1 5EH, UK.
authors: Christoph H
authors: CH
authors: Emmerich
authors: MRC Protein Phosphorylation and ubiquitylation Unit, School of Life Sciences, Sir James Black Centre, University of Dundee, Dow St, Dundee, DD1 5EH, UK.
authors: Sam
authors: S
authors: Strickson
authors: MRC Protein Phosphorylation and ubiquitylation Unit, School of Life Sciences, Sir James Black Centre, University of Dundee, Dow St, Dundee, DD1 5EH, UK.
authors: Maria Stella
authors: MS
authors: Ritorto
authors: Division of Cell Signaling and Immunology, School of Life Sciences, Wellcome Trust Building, University of Dundee, Dow St, Dundee, DD1 5EH, UK.
authors: Ruhcha V
authors: RV
authors: Sutavani
authors: Division of Cell Signaling and Immunology, School of Life Sciences, Wellcome Trust Building, University of Dundee, Dow St, Dundee, DD1 5EH, UK.
authors: Anne
authors: A
authors: Weiβ
authors: Division of Cell Signaling and Immunology, School of Life Sciences, Wellcome Trust Building, University of Dundee, Dow St, Dundee, DD1 5EH, UK.
authors: Kirsty F
authors: KF
authors: Houslay
authors: MRC Protein Phosphorylation and ubiquitylation Unit, School of Life Sciences, Sir James Black Centre, University of Dundee, Dow St, Dundee, DD1 5EH, UK.
authors: Axel
authors: A
authors: Knebel
authors: Cardiovascular and Diabetes Medicine, Medical Research Institute, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, DD1 9SY, UK.
authors: Paul J
authors: PJ
authors: Meakin
authors: Division of Cell Signaling and Immunology, School of Life Sciences, Wellcome Trust Building, University of Dundee, Dow St, Dundee, DD1 5EH, UK.
authors: Iain R
authors: IR
authors: Phair
authors: Cardiovascular and Diabetes Medicine, Medical Research Institute, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, DD1 9SY, UK.
authors: Michael L J
authors: ML
authors: Ashford
authors: MRC Protein Phosphorylation and ubiquitylation Unit, School of Life Sciences, Sir James Black Centre, University of Dundee, Dow St, Dundee, DD1 5EH, UK.
authors: Matthias
authors: M
authors: Trost
authors: Division of Cell Signaling and Immunology, School of Life Sciences, Wellcome Trust Building, University of Dundee, Dow St, Dundee, DD1 5EH, UK.
authors: J Simon C
authors: JS
authors: Arthur
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D000069462:Dimethyl Fumarate / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D025821:Polyubiquitin / Q000235:genetics / Q000378:metabolism*; D000067996:RAW 264.7 Cells; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D051193:Toll-Like Receptors; D025821:Polyubiquitin; D048052:Mitogen-Activated Protein Kinase 3; D000069462:Dimethyl Fumarate