The RNA-binding protein QKI5 is a direct target of C/EBPα and delays macrophage differentiation.
The RNA-binding protein QKI5 is a direct target of C/EBPα and delays macrophage differentiation.
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DOI：
10.1091/mbc.e11-05-0412
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发表时间：
2012-05
影响因子：
3.3
通讯作者：
Lu Z
中科院分区：
文献类型：
--
作者：
Fu H;Yang G;Wei M;Liu L;Jin L;Lu X;Wang L;Shen L;Zhang J;Lu H;Yao L;Lu Z
在单核细胞-巨噬细胞分化过程中，C/EBPα转录激活QKI， QKI反过来抑制CSF1R，从而对C/EBPα诱导的巨噬细胞分化提供负反馈。这种反馈回路对于保持细胞增殖和分化之间的平衡是很重要的。分化的巨噬细胞对先天免疫系统至关重要；然而，巨噬细胞产生的分子机制在很大程度上仍然未知。本研究表明，当CCAAT/增强子结合蛋白(C/EBP) α表达时，rna结合蛋白QKI，主要是QKI-5，在早期分化的单核细胞祖细胞中被转录激活。强迫表达C/EBPα增加内源性QKI的表达。染色质免疫沉淀分析和报告基因分析进一步证实，C/EBPα主要通过结合远端C/EBPα结合位点激活QKI的转录。通过RNA干扰阻断QKI的诱导，增强内源性CSF1R的表达，促进巨噬细胞分化。进一步的机制研究表明，QKI-5通过与远端3 '非翻译区QRE相互作用促进CSF1R mRNA的降解。综上所述，我们发现在巨噬细胞祖细胞中，C/ ebp α激活的QKI-5通过下调CSF1R表达负向调控巨噬细胞分化，在巨噬细胞分化过程中形成负反馈回路。
During monocyte–macrophage differentiation, C/EBPα transcriptionally activates QKI, which in turn represses CSF1R and thus provides negative feedback to C/EBPα-induced macrophage differentiation. This feedback loop should be important in keeping the balance between cell proliferation and differentiation. 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.