The Mouse-Specific Splice Variant mRAGE_v4 Encodes a Membrane-Bound RAGE That Is Resistant to Shedding and Does Not Contribute to the Production of Soluble RAGE
The Mouse-Specific Splice Variant mRAGE_v4 Encodes a Membrane-Bound RAGE That Is Resistant to Shedding and Does Not Contribute to the Production of Soluble RAGE
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DOI：
10.1371/journal.pone.0153832
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发表时间：
2016-09-21
期刊：
影响因子：
3.7
通讯作者：
Raucci, Angela
中科院分区：
文献类型：
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作者：
Di Maggio, Stefania;Gatti, Elena;Raucci, Angela
晚期糖基化终产物受体（RAGE）参与了几种炎症性疾病的发生和进展。RAGE初级转录本经历了许多选择性剪接（AS）事件，其中一些是物种特异性的。在这里，我们描述了小鼠特异性的mRAGE_v4剪接变体，该变体在啮齿动物中保守，在灵长类动物中不存在。mRAGE_v4源于第9外显子跳跃，编码跨膜和免疫球蛋白（Ig）结构域之间缺少9个氨基酸的受体（M-RAGE）。RNA-Seq数据证实，在小鼠肺中，mRAGE_v4是mRAGE之后最丰富的RAGE mRNA亚型，它编码全长RAGE (FL-RAGE)，而在心脏中，几乎检测不到所有RAGE变体。M-RAGE和FL-RAGE蛋白在小鼠肺中的含量大致相当。与FL-RAGE相反，M-RAGE具有极强的抗脱落性，因为它缺乏ADAM10和MMP9都能识别的肽基序，并且对可溶性cRAGE的形成没有显著贡献。因此，RAGE中的盒式外显子对应于RAGE蛋白的一种特定功能——脱落能力。鉴于啮齿动物和人类之间RAGE AS变异的差异，在解释RAGE依赖性人类病理小鼠模型中获得的结果时应谨慎。
The receptor for advanced glycation end-products (RAGE) is involved in the onset and progression of several inflammatory diseases. The RAGE primary transcript undergoes numerous alternative splicing (AS) events, some of which are species-specific. Here, we characterize the mouse-specific mRAGE_v4 splice variant, which is conserved in rodents and absent in primates. mRAGE_v4 derives from exon 9 skipping and encodes a receptor (M-RAGE) that lacks 9 amino acids between the transmembrane and the immunoglobulin (Ig) domains. RNA-Seq data confirm that in mouse lung mRAGE_v4 is the most abundant RAGE mRNA isoform after mRAGE, which codes for full-length RAGE (FL-RAGE), while in heart all RAGE variants are almost undetectable. The proteins M-RAGE and FL-RAGE are roughly equally abundant in mouse lung. Contrary to FL-RAGE, M-RAGE is extremely resistant to shedding because it lacks the peptide motif recognized by both ADAM10 and MMP9, and does not contribute significantly to soluble cRAGE formation. Thus, a cassette exon in RAGE corresponds to a specific function of the RAGE protein-the ability to be shed. Given the differences in RAGE AS variants between rodents and humans, caution is due in the interpretation of results obtained in mouse models of RAGE-dependent human pathologies.