Moyamoya disease susceptibility gene RNF213 links inflammatory and angiogenic signals in endothelial cells.

Kazuhiro Ohkubo,Yasunari Sakai,Hiroyuki Torisu,Yuki Matsushita,Yoshito Ishizaki,Kenji Ihara,Toshiro Hara,Hirosuke Inoue,Marco Sardiello,Satoshi Akamine,Masafumi Sanefuji

doi:10.1038/srep13191

Kazuhiro Ohkubo, Yasunari Sakai + Show 9 more

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https://doi.org/10.1038/srep13191

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Moyamoya disease (MMD) is a cerebrovascular disorder characterized by occlusive lesions of the circle of Willis. To date, both environmental and genetic factors have been implicated for pathogenesis of MMD. Allelic variations in RNF213 are known to confer the risk of MMD; however, functional roles of RNF213 remain to be largely elusive. We herein report that pro-inflammatory cytokines, IFNG and TNFA, synergistically activated transcription of RNF213 both in vitro and in vivo. Using various chemical inhibitors, we found that AKT and PKR pathways contributed to the transcriptional activation of RNF213. Transcriptome-wide analysis and subsequent validation with quantitative PCR supported that endogenous expression of cell cycle-promoting genes were significantly decreased with knockdown of RNF213 in cultured endothelial cells. Consistently, these cells showed less proliferative and less angiogenic profiles. Chemical inhibitors for AKT (LY294002) and PKR (C16) disrupted their angiogenic potentials, suggesting that RNF213 and its upstream pathways cooperatively organize the process of angiogenesis. Furthermore, RNF213 down-regulated expressions of matrix metalloproteases in endothelial cells, but not in fibroblasts or other cell types. Altogether, our data illustrate that RNF213 plays unique roles in endothelial cells for proper gene expressions in response to inflammatory signals from environments.

Highlights

RNF213 gene encompasses a 137,922-bp region at chromosome 17q25.3 and consists of 68 exons with 67 protein-coding exons
RNF213 has been reported to be associated with angiogenesis[14]; little is known about its endogenous functions or its pathogenic roles in MMD13,15
We reasoned that identifying endogenous functions of RNF213 would facilitate our work towards unraveling the pathogenic mechanisms of MMD

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Introduction

RNF213 gene encompasses a 137,922-bp region at chromosome 17q25.3 (chr17:78,234,660–78,372,581) and consists of 68 exons with 67 protein-coding exons. Because of the presence of ring finger domain(s), RNF213 is considered a member of E3 ubiquitin ligase protein family. RNF213 has been reported to be associated with angiogenesis[14]; little is known about its endogenous functions or its pathogenic roles in MMD13,15. To uncover the functional roles of RNF213 and pathogenic processes underlying MMD, we took advantage of bioinformatics approaches to analyze hundreds of transcriptomic data publicly available at open databases[16]. The bioinformatics data predicted that RNF213 might act cooperatively with other molecules under inflammatory signals. Through a series of functional studies, we propose that RNF213 links the gap between environmental risk factors for the onset of MMD and endogenous signaling that is essential for angiogenesis

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