CNBP acts as a key transcriptional regulator of sustained expression of interleukin-6

Abstract

The transcription of inflammatory genes is an essential step in host defense activation. Here, we show that cellular nucleic acid-binding protein (CNBP) acts as a transcription regulator that is required for activating the innate immune response. We identified specific CNBP-binding motifs present in the promoter region of sustained inflammatory cytokines, thus, directly inducing the expression of target genes. In particular, lipopolysaccharide (LPS) induced cnbp expression through an NF-κB-dependent manner and a positive autoregulatory mechanism, which enables prolonged il-6 gene expression. This event depends strictly on LPS-induced CNBP nuclear translocation through phosphorylation-mediated dimerization. Consequently, cnbp-depleted zebrafish are highly susceptible to Shigella flexneri infection in vivo. Collectively, these observations identify CNBP as a key transcriptional regulator required for activating and maintaining the immune response.

CNBP controls tumor cell biology by regulating tumor‐promoting gene expression

“…Because EGF triggers PKC activation, we further explored whether PKC phosphorylated CNBP in response to EGF. As previously noted, in vitro kinase assay showed that PKC phosphorylated CNBP as well as the NF‐κB subunit p65 (Figure S2). To determine whether EGF‐stimulated PKC induced CNBP nuclear translocation, we measured the amount of CNBP in the cytosolic and nuclear fractions from TC‐1 cells stimulated with EGF after pretreatment with the PKC inhibitor BIM‐I.…”

“…We previously identified the specific CNBP‐binding motif sequence of CTGAAAAt(a), which is present in the promotors of its target inflammatory genes . Interestingly, the promoter regions of tumor‐related genes , such as mmp‐2 , kras , mmp‐14 , and e2f2 also contained a very similar motif alignment essential for CNBP binding (Figure A and Doc S2).…”

“…These findings led us to ask why there was a difference in the binding ability of CNBP between mmp‐2 / mmp‐14 / e2f2 and kras , despite their promoters all possessing the same CNBP‐binding core sequences (GAAAA) E).…”

“…It is broadly known that posttranslational modifications, including phosphorylation, ubiquitination, and dimerization, regulate the nuclear translocation of transcription factors. Our previous study showed that threonine (Thr) residues positioned at 173 and 177 of CNBP were indispensable for its phosphorylation and dimerization in response to lipopolysaccharide (LPS) exposure, leading to nuclear translocation . Therefore, we speculated that EGF would induce CNBP phosphorylation at Thr residues 173 and 177; however, neither Thr residue was involved in EGF‐mediated mmp‐2 expression, CNBP phosphorylation, and its dimerization (Figure S2).…”

“…CNBP has been implicated in diverse biological processes, acting as a nucleic acid chaperone and transcription factor. Several studies have shown that CNBP regulates the expression of macrophage colony‐stimulating factor ( csf1 ), c‐myc proto‐oncogene, Wnt signaling pathway components, and proinflammatory cytokines . In addition, CNBP is involved in embryonic forebrain development and various human diseases, including myotonic dystrophy type 2 (DM2) and sporadic inclusion body myositis (sIBM) .…”