Fascin Regulates TLR4/PKC-mediated Translational Activation Through miR-155 and miR-125b, which Targets the 3′ Untranslated Region of TNF-α mRNA

Abstract

Fascin is a well-known cytoskeletal regulatory protein that, as a substrate of protein kinase C (PKC), is involved in PKC-mediated translational regulation of TNF-α in macrophages stimulated with lipopolysaccharide (LPS). The regulatory effects of fascin targeted the 3′-untraslated region (UTR) of the TNF-α mRNA, and suppression of PKC activity or fascin expression resulted in specific blockage of the LPS-induced translational activation of the mRNA. In an effort to identify the molecular mechanism of this fascin-mediated translational regulation, the expression levels of micro-RNA (miRNA) after stimulation of the toll-like receptor 4 (TLR4) signaling pathways were analyzed in cells with down-regulation of fascin. The LPS-induced translation of TNF-α is known to be regulated by miR-155 and miR-125b, which have positive and negative effects, respectively. Interestingly, suppression of fascin expression reversed LPS-induced down-regulation of miR-125b and abolished the LPS-induced increase in miR-155. Furthermore, introduction of miR-155 precursor, blocking of miR-125b activity, or introduction of a mutation into the miR-125b binding site of the TNF-α 3′-UTR restored translational activation in cells with suppressed fascin expression. These data indicate that fascin regulates translation through miR-155 and miR-125b, which target 3′ UTR in TNF-α mRNA.

• Fascin
• miR-155
• miR-125b
• TNF-α
• translational regulation

Declaration of interest

This study was supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012R1A1A4A01005809 and 2014R1A1A2053381).

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.