德国哈勒-维腾贝格大学Marcel Köhn研究小组发现，Rbfox1控制心肌细胞中黏着斑基因的可变剪接。2024年1月22日，国际知名学术期刊《分子细胞生物学报》在线发表了这一成果。

研究人员报道了心肌中剪接因子Rbfox1的靶标谱。通过结合使用计算靶标预测和细胞内验证，研究人员确定了几种黏着斑蛋白是Rbfox1的可变剪接靶标。研究人员重点揭示了Vinculin（Metavinculin亚型）和Paxillin（扩展的Paxillin亚型）的可变剪接模式，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亚型的形成。黏着斑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。

数据证实，去除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，这可能是由于黏着斑蛋白的可变剪接发生了变化。因此，这些研究结果表明，Rbfox1促进了心肌细胞中黏着斑基因的可变剪接，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。

据了解，可变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，鉴定由可变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。

附：英文原文

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

Author: Zorn, Peter, Calvo Sánchez, Jaime, Alakhras, Tala, Schreier, Barbara, Gekle, Michael, Hüttelmaier, Stefan, Khn, Marcel

Issue&Volume: 2024-01-22

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.

DOI: 10.1093/jmcb/mjae003

Source: https://dx.doi.org/10.1093/jmcb/mjae003