The RNA-binding protein Tristetraprolin (TTP) is a critical negative regulator of the NLRP3 inflammasome.
2017
Abstract The NLRP3
inflammasomeis 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 elementsin 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-1and IL-1β cleavage upon NLRP3, but not
AIM2or
NLRC4
inflammasomeactivation. 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.
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