Rbfox1 controls alternative splicing of focal adhesion genes in cardiac muscle cells.

IF 5.3 2区 生物学 Q2 CELL BIOLOGY Journal of Molecular Cell Biology Pub Date : 2024-07-01 DOI:10.1093/jmcb/mjae003
Peter Zorn, Jaime Calvo Sánchez, Tala Alakhras, Barbara Schreier, Michael Gekle, Stefan Hüttelmaier, Marcel Köhn
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Abstract

Alternative splicing is one of the major cellular processes that determine the tissue-specific expression of protein variants. However, it remains challenging to identify physiologically relevant and tissue-selective proteins that are generated by alternative splicing. Hence, we investigated the target spectrum of the splicing factor Rbfox1 in the cardiac muscle context in more detail. By using a combination of in silico target prediction and in-cell validation, we identified several focal adhesion proteins as alternative splicing targets of Rbfox1. We focused on the alternative splicing patterns of vinculin (metavinculin isoform) and paxillin (extended paxillin isoform) and identified both as potential Rbfox1 targets. Minigene analyses suggested that both isoforms are promoted by Rbfox1 due to binding in the introns. Focal adhesions play an important role in the cardiac muscle context, since they mainly influence cell shape, cytoskeletal organization, and cell-matrix association. Our data confirmed that depletion of Rbfox1 changed cardiomyoblast morphology, cytoskeletal organization, and multinuclearity after differentiation, which might be due to changes in alternative splicing of focal adhesion proteins. Hence, our results indicate that Rbfox1 promotes alternative splicing of focal adhesion genes in cardiac muscle cells, which might contribute to heart disease progression, where downregulation of Rbfox1 is frequently observed.

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Rbfox1 控制着心肌细胞中局灶粘附基因的替代剪接。
替代剪接是决定蛋白质变体组织特异性表达的主要细胞过程之一。然而,鉴定由替代剪接产生的生理相关性和组织选择性蛋白质仍然具有挑战性。因此,我们更详细地研究了心肌中剪接因子 Rbfox1 的目标谱。通过结合使用硅学靶标预测和细胞内验证,我们确定了几种局灶粘附蛋白是 Rbfox1 的替代剪接靶标。我们重点研究了Vinculin(Metavinculin异构体)和Paxillin(扩展的Paxillin异构体)的替代剪接模式,并发现这两种蛋白都是Rbfox1的潜在靶标。微型基因分析表明,Rbfox1通过与内含子结合促进了这两种异构体的形成。病灶粘连在心肌中起着重要作用,因为它们主要影响细胞形状、细胞骨架组织和细胞与基质的结合。我们的数据证实,耗尽 Rbfox1 会改变心肌母细胞的形态、细胞骨架组织和分化后的多核性,这可能是由于局灶粘附蛋白的替代剪接发生了变化。因此,我们的研究结果表明,Rbfox1 促进了心肌细胞中局灶粘附基因的替代剪接,这可能是导致心脏病进展的原因之一,而在心脏病中经常观察到 Rbfox1 的下调。
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来源期刊
CiteScore
9.60
自引率
1.80%
发文量
1383
期刊介绍: The Journal of Molecular Cell Biology ( JMCB ) is a full open access, peer-reviewed online journal interested in inter-disciplinary studies at the cross-sections between molecular and cell biology as well as other disciplines of life sciences. The broad scope of JMCB reflects the merging of these life science disciplines such as stem cell research, signaling, genetics, epigenetics, genomics, development, immunology, cancer biology, molecular pathogenesis, neuroscience, and systems biology. The journal will publish primary research papers with findings of unusual significance and broad scientific interest. Review articles, letters and commentary on timely issues are also welcome. JMCB features an outstanding Editorial Board, which will serve as scientific advisors to the journal and provide strategic guidance for the development of the journal. By selecting only the best papers for publication, JMCB will provide a first rate publishing forum for scientists all over the world.
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