The RNA-binding protein Tristetraprolin (TTP) is a critical negative regulator of the NLRP3 inflammasome

Research output: Contribution to journalArticlepeer-review

Authors

  • Moritz Haneklaus
  • John O'Neil
  • Andrew R Clark
  • Seth L Masters
  • Luke A J O'Neill

Colleges, School and Institutes

External organisations

  • From the School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
  • the Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom, and.
  • the Inflammation Division, The Walter and Eliza Hall Institute, Melbourne, Victoria 3052, Australia.
  • From the School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland, laoneill@tcd.ie.

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 the NLRP3 3'-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 human NLRP3 can 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.

Details

Original languageEnglish
Pages (from-to)6869-6881
Number of pages13
JournalJournal of Biological Chemistry
Volume292
Issue number17
Early online date16 Mar 2017
Publication statusPublished - 28 Apr 2017

Keywords

  • Journal Article