Jain Mamta, Manjaly Greeshma, Maly Kathrin, de Vries Margreet R, Janisiw Michael, König Lisa, Nossent Anne Yaël, Jantsch Michael F
Medical University of Vienna, Center of Anatomy and Cell Biology, Division of Cell and Developmental Biology, Schwarzspanierstrasse 17, 1090 Vienna, Austria.
Leiden University Medical Center, Department of Surgery, Einthoven Laboratory for Experimental Vascular Medicine, PO Box 9600, 2300 RC Leiden, the Netherlands.
Mol Ther Nucleic Acids. 2022 Nov 9;30:522-534. doi: 10.1016/j.omtn.2022.11.004. eCollection 2022 Dec 13.
Adenosine to inosine (A to I) editing is mediated by adenosine deaminases acting on RNA (ADAR) enzymes. Inosines are interpreted as guanosines by the translational machinery. Consequently, A to I editing in mRNAs can lead to their recoding and the formation of proteins not encoded in the genome. Filamin A is an actin-crosslinking protein. A to I editing in the filamin pre-mRNA leads to the exchange of a glutamine to an arginine in a highly interactive domain of the protein. However, the consequences of this editing event are still poorly understood. Here we show, using transgenic mice expressing either constitutively edited or constitutively uneditable filamin A that filamin A editing critically controls angiogenesis in tumors but also in a mouse ischemia model. Hyper-editing reduces angiogenesis, while hypoediting leads to increased angiogenesis, possibly by altering vascular endothelial growth factor receptor 2 (VEGFR2) turnover. Further, FLNA editing of the tumor itself seemingly affects its metastatic potential by changing its interaction with the extracellular matrix. We therefore identify filamin A editing as a critical component for angiogenesis, tumor growth, and metastasis formation.
腺苷到肌苷（A到I）的编辑由作用于RNA的腺苷脱氨酶（ADAR）介导。肌苷在翻译过程中被解读为鸟苷。因此，mRNA中的A到I编辑可导致其重新编码并形成基因组中未编码的蛋白质。细丝蛋白A是一种肌动蛋白交联蛋白。细丝蛋白前体mRNA中的A到I编辑导致该蛋白一个高度相互作用结构域中的谷氨酰胺被精氨酸取代。然而，这一编辑事件的后果仍知之甚少。在此，我们利用表达组成型编辑或组成型不可编辑细丝蛋白A的转基因小鼠表明，细丝蛋白A编辑对肿瘤血管生成至关重要，在小鼠缺血模型中也是如此。过度编辑会减少血管生成，而编辑不足则会导致血管生成增加，这可能是通过改变血管内皮生长因子受体2（VEGFR2）的周转来实现的。此外，肿瘤本身的FLNA编辑似乎通过改变其与细胞外基质的相互作用来影响其转移潜能。因此，我们确定细丝蛋白A编辑是血管生成、肿瘤生长和转移形成的关键组成部分。
