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

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

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)
150 Downloads (Pure)

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.

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

Keywords

  • Journal Article

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