Eswarappa Sandeepa M, Potdar Alka A, Koch William J, Fan Yi, Vasu Kommireddy, Lindner Daniel, Willard Belinda, Graham Linda M, DiCorleto Paul E, Fox Paul L
Department of Cellular and Molecular Medicine, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Department of Cellular and Molecular Medicine, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA.
Cell. 2014 Jun 19;157(7):1605-18. doi: 10.1016/j.cell.2014.04.033.
Translational readthrough, observed primarily in less complex organisms from viruses to Drosophila, expands the proteome by translating select transcripts beyond the canonical stop codon. Here, we show that vascular endothelial growth factor A (VEGFA) mRNA in mammalian endothelial cells undergoes programmed translational readthrough (PTR) generating VEGF-Ax, an isoform containing a unique 22-amino-acid C terminus extension. A cis-acting element in the VEGFA 3' UTR serves a dual function, not only encoding the appended peptide but also directing the PTR by decoding the UGA stop codon as serine. Heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 binds this element and promotes readthrough. Remarkably, VEGF-Ax exhibits antiangiogenic activity in contrast to the proangiogenic activity of VEGF-A. Pathophysiological significance of VEGF-Ax is indicated by robust expression in multiple human tissues but depletion in colon adenocarcinoma. Furthermore, genome-wide analysis revealed AGO1 and MTCH2 as authentic readthrough targets. Overall, our studies reveal a novel protein-regulated PTR event in a vertebrate system.
翻译通读主要在从病毒到果蝇等较为简单的生物体中观察到，它通过翻译某些转录本越过经典终止密码子来扩展蛋白质组。在此，我们表明哺乳动物内皮细胞中的血管内皮生长因子A（VEGFA）mRNA经历程序性翻译通读（PTR），产生VEGF-Ax，这是一种含有独特的22个氨基酸C末端延伸的异构体。VEGFA 3'UTR中的一个顺式作用元件具有双重功能，不仅编码附加肽，还通过将UGA终止密码子解码为丝氨酸来指导翻译通读。异质性核核糖核蛋白（hnRNP）A2/B1结合该元件并促进通读。值得注意的是，与VEGF-A的促血管生成活性相反，VEGF-Ax表现出抗血管生成活性。VEGF-Ax在多种人类组织中大量表达，但在结肠腺癌中缺失，这表明了其病理生理学意义。此外，全基因组分析揭示AGO1和MTCH2是真正的通读靶点。总体而言，我们的研究揭示了脊椎动物系统中一种新型的蛋白质调节的翻译通读事件。
