The RNA-binding protein QKI5 is a direct target of C/EBPα and delays macrophage differentiation

Abstract

<jats:p>Differentiated macrophages are essential for the innate immune system; however, the molecular mechanisms underlying the generation of macrophages remain largely unknown. Here we show that the RNA-binding protein QKI, mainly QKI-5, is transcriptionally activated in the early differentiated monocytic progenitors when CCAAT/enhancer-binding protein (C/EBP) α is expressed. The forced expression of C/EBPα increases the endogenous expression of QKI. Chromatin immunoprecipitation analysis and reporter assays further confirm that C/EBPα activates the transcription of QKI, primarily by binding to the distal C/EBPα-binding site. Blocking the induction of QKI using RNA interference enhances the expression of endogenous CSF1R and facilitates macrophage differentiation. Further study of the mechanism reveals that QKI-5 facilitates the degradation of CSF1R mRNA by interacting with the distal QRE in the 3′ untranslated region. In summary, we show that in committed macrophage progenitors, C/EBPα-activated QKI-5 negatively regulates macrophage differentiation by down-regulating CSF1R expression, forming a negative feedback loop during macrophage differentiation.</jats:p>

miR-29a promotes scavenger receptor A expression by targeting QKI (quaking) during monocyte-macrophage differentiation

“…This observation was consistent with previous published studies involving miR-29a and QKI [11,21]. On further analysis, it was identified that QKI has mir-29a binding sites in 3 0 UTR of its mRNA.…”

“…In this study, we have tried to elucidate a novel mechanism that regulates SRA expression. Based on the previously published studies by us and other labs, it has been shown that during monocyte differentiation into macrophages, a) QKI expression is inhibited [11,5], and, b) miR-29a enhanced SRA expression [5,18]. So, this led us to ask a question, how miR-29a is regulating SRA expression and is it possible that these three genes are inter-related in terms of their regulation of each other.…”

“…During monocyte differentiation into macrophage, its expression is down regulated [11]. Bioinformatics data suggest that mRNA of SRA gene contains QRE (quaking response element) at its 3 0 UTR region.…”

“…Next, the PCR products of QKI and SRA 3 0 UTR regions containing wildtype and mutant binding sites [11]of miR-29a or QRE respectively were gel purified. After purification, they were ligated into pGL3 vector (Promega) between HindIII and SacI restriction sites.…”

Post-transcriptional repression of FOXO1 by QKI results in low levels of FOXO1 expression in breast cancer cells

“…In adult mammals, qki mRNAs can be detected in tissues, such as the heart, skeletal, lung, testes and immune cells in addition to the central nervous system (CNS) (9,(12)(13)(14)(15). In a search for putative RNA targets recognized by QKI, a bipartite consensus sequence ACUAAY-N(1-20)-UAAY was defined as a QKI response element (QRE), and 1,430 putative mRNA targets were identified by bioinformatic analysis (16).…”