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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
): 6869-6881
PMID28302726
show 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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