title: The RNA-binding protein Tristetraprolin (TTP) is a critical negative regulator of the NLRP3 inflammasome.
abstract: The NLRP3 inflammasome is a central regulator of inflammation in many common diseases, including atherosclerosis and type 2 diabetes, driving the production of pro-inflammatory mediators such as IL-1β and IL-18. Due to its function as an inflammatory gatekeeper, expression and activation of NLRP3 need to be tightly regulated. In this study, we highlight novel post-transcriptional mechanisms that can modulate NLRP3 expression. We have identified the RNA-binding protein Tristetraprolin (TTP) as a negative regulator of NLRP3 in human macrophages. TTP targets AU-rich elements in theNLRP33'-untranslated region (UTR) and represses NLRP3 expression. Knocking down TTP in primary macrophages leads to an increased induction of NLRP3 by LPS, which is also accompanied by increased Caspase-1 and IL-1β cleavage upon NLRP3, but not AIM2 or NLRC4 inflammasome activation. Furthermore, we found that humanNLRP3can be alternatively polyadenylated, producing a short 3'-UTR isoform that excludes regulatory elements, including the TTP- and miRNA-223-binding sites. Because TTP also represses IL-1β expression, it is a dual inhibitor of the IL-1β system, regulating expression of the cytokine and the upstream controller NLRP3.
authors.affiliation: From the School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Moritz
authors.identifier: 0000-0003-1529-9677
authors.initials: M
authors.lastname: Haneklaus
authors.affiliation: the Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom, and.
authors.forename: John D
authors.initials: JD
authors.lastname: O'Neil
authors.affiliation: the Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom, and.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Clark
authors.affiliation: the Inflammation Division, The Walter and Eliza Hall Institute, Melbourne, Victoria 3052, Australia.
authors.forename: Seth L
authors.initials: SL
authors.lastname: Masters
authors.affiliation: From the School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland, laoneill@tcd.ie.
authors.forename: Luke A J
authors.initials: LAJ
authors.lastname: O'Neill
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D051816:Tristetraprolin / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D051816:Tristetraprolin; D020170:Caspase 1
keywords: NLRP3; TTP; Tristetraprolin; inflammasome; inflammation; interleukin 1 (IL-1); macrophage; post-transcriptional regulation