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

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-1 (cid:2) 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 (cid:2) -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 accompa-nied by increased Caspase-1 and IL-1 (cid:2) cleavage upon NLRP3, but not AIM2 or NLRC4 inflammasome activation. Further-more, we found that human NLRP3 can be alternatively polyadenylated, producing a short 3 (cid:2) -UTR isoform that excludes regulatory elements, including the TTP-

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