A GPI anchor explains the unique biological features of the common NKG2D-ligand allele MICA*008
A GPI anchor explains the unique biological features of the common NKG2D-ligand allele MICA*008
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DOI：
10.1042/bj20130194
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发表时间：
2013-09-01
影响因子：
4.1
通讯作者：
Vales-Gomez, Mar
中科院分区：
文献类型：
--
作者：
Ashiru, Omodele;Lopez-Cobo, Sheila;Vales-Gomez, Mar
人类云母（MHC I相关链A）基因编码NKG 2D（NKG 2-D II型整合膜蛋白）受体的配体，具有高度多态性。一组名为云母5.1（原型，云母 *008）的云母等位基因由于跨膜结构域中的核苷酸插入而产生截短的蛋白质。这些等位基因在研究的所有人群中非常常见，与全长等位基因相比，它们具有不同的生物学特性，例如募集到外泌体中，这使得它们非常有效地下调效应免疫细胞中的NKG 2D受体。此外，云母 *008不受靶向其他云母等位基因的病毒免疫逃避机制的影响。在本研究中，我们证明了云母 *008获得了GPI（糖基磷脂酰肌醇）锚，并且这种修饰是截短的云母等位基因的许多独特生物学特征的原因，包括蛋白质向外泌体的募集。云母 *008的加工也是不寻常的，因为在内质网中观察到它作为Triton（TM）X-114可溶性蛋白，部分经历GPI修饰，而其余部分被胞吐，这表明云母 *008释放的新模型。这是第一个报告的GPI锚定的云母等位基因。这种修饰发生在人NKG 2D配体的两个家族以及鼠系统中，这一发现表明正压力可以维持这种生化特征。
The human MICA (MHC I-related chain A) gene, encoding a ligand for the NKG2D (NKG2-D type II integral membrane protein) receptor, is highly polymorphic. A group of MICA alleles, named MICA 5.1 (prototype, MICA*008), produce a truncated protein due to a nucleotide insertion in the transmembrane domain. These alleles are very frequent in all of the human populations studied and they have different biological properties, compared with full-length alleles, e.g. recruitment into exosomes, which makes them very potent for down-modulating the NKG2D receptor in effector immune cells. Moreover, MICA*008 is not affected by viral immune evasion mechanisms that target other MICA alleles. In the present study, we demonstrate that MICA*008 acquires a GPI (glycosylphosphatidylinositol) anchor and that this modification is responsible for many of the distinct biological features of the truncated MICA alleles, including recruitment of the protein to exosomes. MICA*008 processing is also unusual as it is observed in the endoplasmic reticulum as a Triton (TM) X-114 soluble protein, partially undergoing GPI modification while the rest is exocytosed, suggesting a new model for MICA*008 release. This is the first report of a GPI-anchored MICA allele. The finding that this modification occurs in both families of human NKG2D ligands, as well as in the murine system, suggests positive pressure to maintain this biochemical feature.