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10.1074/jbc.M116.772947

http://scihub22266oqcxt.onion/10.1074/jbc.M116.772947
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C5409458!5409458!28302726
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suck abstract from ncbi


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pmid28302726      J+Biol+Chem 2017 ; 292 (17): 6869-81
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  • The RNA-binding protein Tristetraprolin (TTP) is a critical negative regulator of the NLRP3 inflammasome #MMPMID28302726
  • Haneklaus M; O'Neil JD; Clark AR; Masters SL; O'Neill LAJ
  • J Biol Chem 2017[Apr]; 292 (17): 6869-81 PMID28302726show ga
  • 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? 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-1? 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-1? expression, it is a dual inhibitor of the IL-1? system, regulating expression of the cytokine and the upstream controller NLRP3.
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