The RNA-binding protein Tristetraprolin (TTP) is a critical negative regulator of the NLRP3 inflammasome
- Author(s)
- Haneklaus, M; O'Neil, JD; Clark, AR; Masters, SL; O'Neill, LA;
- Details
- Publication Year 2017-04-28,Volume 292,Issue #17,Page 6869-6881
- Journal Title
- Journal of Biological Chemistry
- Publication Type
- Journal Article
- 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-1beta 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-1beta 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. Since TTP also represses IL-1beta expression, it is a dual inhibitor of the IL-1beta system, regulating expression of the cytokine and the upstream controller NLRP3.
- Publisher
- ASBMB
- Research Division(s)
- Inflammation
- PubMed ID
- 28302726
- Link To PubMed Central Version
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409458/
- Publisher's Version
- https://doi.org/10.1074/jbc.M116.772947
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2017-04-12 10:42:08
Last Modified: 2018-05-07 02:02:36