Elsevier

Cytokine

Volume 63, Issue 3, September 2013, Page 269
Cytokine

111 : Critical role for the 3′UTR in the post-transcriptional regulation of the gene encoding the key inflammasome protein NLRP3

https://doi.org/10.1016/j.cyto.2013.06.114Get rights and content

IL-1β is a potent pro-inflammatory cytokine and its production is tightly controlled by the inflammasomes. For example, the inflammasome that forms around the cytosolic receptor NLRP3 is regulated on many different levels. NLRP3 is triggered by an array of endogenous and exogenous cellular stresses and although the precise mechanism of activation is still little understood, a range of cellular signals, such as calcium signaling and reactive oxygen species, can influence the process. In addition, NLRP3 is regulated transcriptionally by the TLR pathway and by post-translational modifications such as nitrosylation and ubiquitination. We have found that NLRP3 is also post-transcriptionally regulated by a microRNA, miRNA-223. This is important during myeloid differentiation, where miR-223 is differentially expressed. We also found that the NLRP3 3′ untranslated region (UTR) is responsive to LPS and PMA, indicating a post-transcriptional component of the ‘priming signal’. Interestingly, the human NLRP3 mRNA is alternatively polyadenylated, resulting in 3′UTR isoforms of varying length. This enables selective use of regulatory elements by expressing shorter isoforms. Furthermore, in both mouse and human cells, the NLRP3 message is very unstable, which would suggest control by destabilizing RNA binding proteins. These findings provide added insights into control of this important pro-inflammatory system, can help explain cell type-specific expression of NLRP3 and might potentially provide new opportunities to interfere with inflammasome activation in disease such as Type 2 diabetes.

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