Quaking promotes monocyte differentiation into pro-atherogenic macrophages by controlling pre-mRNA splicing and gene expression

Abstract

A hallmark of inflammatory diseases is the excessive recruitment and influx of monocytes to sites of tissue damage and their ensuing differentiation into macrophages. Numerous stimuli are known to induce transcriptional changes associated with macrophage phenotype, but posttranscriptional control of human macrophage differentiation is less well understood. Here we show that expression levels of the RNA-binding protein Quaking (QKI) are low in monocytes and early human atherosclerotic lesions, but are abundant in macrophages of advanced plaques. Depletion of QKI protein impairs monocyte adhesion, migration, differentiation into macrophages and foam cell formation in vitro and in vivo. RNA-seq and microarray analysis of human monocyte and macrophage transcriptomes, including those of a unique QKI haploinsufficient patient, reveal striking changes in QKI-dependent messenger RNA levels and splicing of RNA transcripts. The biological importance of these transcripts and requirement for QKI during differentiation illustrates a central role for QKI in posttranscriptionally guiding macrophage identity and function.

miR‐200/375 control epithelial plasticity‐associated alternative splicing by repressing the RNA ‐binding protein Quaking

“…As both miR-200c and miR-375 act both on the mRNA level and on translation of QKI-5, this ZEB1/miR-200/miR-375/QKI-5 regulatory loop is particularly strong, producing the strongly mesenchymal expression pattern of QKI we observed in the panel of breast cancer cell lines that we examined, paralleling the mutually exclusive expression of miR-200c and ZEB1 . Since QKI has notable functions outside of EMT, including regulating neuronal (Larocque et al, 2005;Zhao et al, 2006;Hayakawa-Yano et al, 2017), smooth muscle and vascular (Noveroske et al, 2002;Li et al, 2003;van der Veer et al, 2013;Cochrane et al, 2017) cell function, and alternative splicing programmes during muscle cell (Hall et al, 2013) and monocyte (de Bruin et al, 2016a) differentiation, we propose that the ZEB1/miR-200c/miR-375/QKI-5 pathway may influence splicing outcomes that impact a broad range of cell differentiation contexts.…”

“…We find here that miR‐200 exerts a widespread influence on alternative splicing during EMT, through its strong regulation of QKI. QKI is a member of the STAR family of RBPs and has been reported to have diverse functions in mRNA stability (Larocque et al , ; Zhao et al , ) and translation (Saccomanno et al , ; de Bruin et al , ), miRNA processing (Wang et al , , ) and alternative splicing (Hall et al , ; van der Veer et al , ; Zong et al , ; de Bruin et al , ; Darbelli et al , ; Fagg et al , ; Hayakawa‐Yano et al , ). We have recently shown that QKI can promote circular RNA formation during EMT (Conn et al , ), although the functional consequences of QKI in EMT remain unclear.…”

Emerging roles of RNA‐binding proteins in diabetes and their therapeutic potential in diabetic complications

“…The alternative splicing (AS) regulators CELF1, RBFOX2, RBFOX1, QKI, and hnRNPC are implicated in diabetes by affecting AS decisions (de Bruin et al, 2016;Guo et al, 2011Guo et al, , 2014Nutter et al, 2016Nutter et al, , 2017Panchenko et al, 2009;van der Veer et al, 2013;Verma et al, 2013). Splicing is a process by which the noncoding regions (introns) of the pre-mRNA are removed and coding regions (exons) are joined together.…”

Inhibition of Osteoclastogenesis by the RNA-Binding Protein QKI5: a Novel Approach to Protect from Bone Resorption

“…It also has an impact on mRNA stability and translation . Moreover, QKI5 has been shown to play a role in microRNA stabilization, muscle differentiation, and monocyte to macrophage differentiation . Indeed, it has been described that, in different contexts, QKI proteins could promote differentiation of monocytes into pro‐atherogenic macrophages or, conversely, inhibit macrophage differentiation .…”