A novel splice variant of human L-selectin encodes a soluble molecule that is elevated in serum of patients with rheumatic diseases
A novel splice variant of human L-selectin encodes a soluble molecule that is elevated in serum of patients with rheumatic diseases
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DOI：
10.1016/j.bbrc.2015.05.002
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发表时间：
2015-07-10
影响因子：
3.1
通讯作者：
Mimori, Tsuneyo
中科院分区：
文献类型：
--
作者：
Hirata, Takako;Usui, Takashi;Mimori, Tsuneyo
L-选择素是一种 I 型膜蛋白，是一种白细胞粘附分子，介导淋巴细胞归巢至外周淋巴结以及白细胞在炎症部位的积聚。 L-选择素在细胞激活后迅速从细胞表面脱落，由此释放的胞外域被认为是血清中高水平可溶性L-选择素的原因。在这项研究中，我们报告了人类 L-选择素基因的一种新的、天然存在的亚型的鉴定。序列分析表明，该亚型是由选择性剪接事件产生的：人类 L-选择素基因的第 7 个外显子（编码包含跨膜结构域的区域）被排除，预测会产生可溶性蛋白质产物。该剪接变体的 mRNA 在淋巴器官中表达，其中也表达了常规的 L-选择素 mRNA。激活 T 细胞会增加变异 mRNA 及其与膜形式的比例。从变异mRNA翻译而来的可溶性L-选择素存在于人血清中，尽管其水平比胞外域脱落产生的水平低得多，并且在患有各种风湿性疾病（包括类风湿性关节炎和系统性红斑狼疮）的患者中显着升高。这些观察结果表明，人血清中存在的一些可溶性 L-选择素是通过选择性剪接产生的，这些剪接可能在患有各种临床病症的患者的淋巴细胞活化过程中上调。 (C) 2015 Elsevier Inc. 保留所有权利。
L-selectin, a type I membrane protein, is a leukocyte adhesion molecule that mediates both lymphocyte homing to peripheral lymph nodes and leukocyte accumulation at sites of inflammation. L-selectin is rapidly shed from the cell surface after cellular activation, and the ectodomain thus released is thought to account for high levels of soluble L-selectin in serum. In this study, we report the identification of a novel, naturally occurring isoform of the human L-selectin gene. Sequence analysis revealed that this isoform is generated by an alternative splicing event: the 7th exon of the human L-selectin gene, which encodes the region containing the transmembrane domain, is excluded, predicting a soluble protein product. The mRNA for this splice variant was expressed in lymphoid organs, where conventional L-selectin mRNA was also expressed. Activating T cells increased the variant mRNA and its ratio to the membrane form. Soluble L-selectin translated from the variant mRNA was present in human serum, albeit at a much lower level than that arising from ectodomain shedding, and was markedly elevated in patients with various rheumatic diseases, including rheumatoid arthritis and systemic lupus erythematosus. These observations indicate that some of the soluble L-selectin present in human serum arises through alternative splicing, which may be upregulated during lymphocyte activation in patients with various clinical conditions. (C) 2015 Elsevier Inc. All rights reserved.