title: Deubiquitinases regulate the activity of caspase-1 and interleukin-1β secretion via assembly of the inflammasome.
abstract: IL-1β is a potent pro-inflammatory cytokine produced in response to infection or injury. It is synthesized as an inactive precursor that is activated by the protease caspase-1 within a cytosolic molecular complex called the inflammasome. Assembly of this complex is triggered by a range of structurally diverse damage or pathogen associated stimuli, and the signaling pathways through which these act are poorly understood. Ubiquitination is a post-translational modification essential for maintaining cellular homeostasis. It can be reversed by deubiquitinase enzymes (DUBs) that remove ubiquitin moieties from the protein thus modifying its fate. DUBs present specificity toward different ubiquitin chain topologies and are crucial for recycling ubiquitin molecules before protein degradation as well as regulating key cellular processes such as protein trafficking, gene transcription, and signaling. We report here that small molecule inhibitors of DUB activity inhibit inflammasome activation. Inhibition of DUBs blocked the processing and release of IL-1β in both mouse and human macrophages. DUB activity was necessary for inflammasome association as DUB inhibition also impaired ASC oligomerization and caspase-1 activation without directly blocking caspase-1 activity. These data reveal the requirement for DUB activity in a key reaction of the innate immune response and highlight the therapeutic potential of DUB inhibitors for chronic auto-inflammatory diseases.
authors.affiliation: AV Hill Building, Faculty of Life Sciences, University of Manchester Manchester, M13 9PT, United Kingdom.
authors.forename: Gloria
authors.initials: G
authors.lastname: Lopez-Castejon
authors.forename: Nadia M
authors.initials: NM
authors.lastname: Luheshi
authors.forename: Vincent
authors.initials: V
authors.lastname: Compan
authors.forename: Stephen
authors.initials: S
authors.lastname: High
authors.forename: Roger C
authors.initials: RC
authors.lastname: Whitehead
authors.forename: Sabine
authors.initials: S
authors.lastname: Flitsch
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Kirov
authors.forename: Igor
authors.initials: I
authors.lastname: Prudovsky
authors.forename: Eileithyia
authors.initials: E
authors.lastname: Swanton
authors.forename: David
authors.initials: D
authors.lastname: Brough
mesh_terms: D000818:Animals; D002268:Carboxypeptidases / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism*; D010450:Endopeptidases / Q000737:chemistry / Q000502:physiology*; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D007113:Immunity, Innate; D007249:Inflammation; D053582:Interleukin-1alpha / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D043222:Ubiquitin Thiolesterase
chemical_list: C492847:1-(4-chlorophenyl)-3-(3-(4-chlorophenyl)-5,5-dimethyl-1-(3-(5-nitrofuran-2-yl)allyldienehydrazinocarbonylmethyl)-2-oxoimidazolidin-4-yl)-1-hydroxyurea; D006835:Hydrazones; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D007378:Interleukins; C509299:USP14 protein, human; C469268:Usp14 protein, mouse; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D002268:Carboxypeptidases; D010450:Endopeptidases; C421245:UCHL5 protein, human; D043222:Ubiquitin Thiolesterase; D020170:Caspase 1; D006918:Hydroxyurea