A basolateral sorting motif in the MICA cytoplasmic tail
A basolateral sorting motif in the MICA cytoplasmic tail
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DOI：
10.1073/pnas.052701099
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发表时间：
2002-03-05
影响因子：
11.1
通讯作者：
Inoko, H
中科院分区：
文献类型：
--
作者：
Suemizu, H;Radosavljevic, M;Inoko, H
MHC I类链相关的MICA分子是一种应激诱导的、高度多态性的、上皮特异性的、膜结合的糖蛋白，与活化的NK细胞受体NKG2D和/或富含vdelta1的肠道γ - T细胞相互作用。我们之前报道了MICA跨膜编码短串联重复序列的存在，其中包含一个特殊的等位基因A5.1，其特征是一个帧移突变导致过早的结构域内停止密码子，从而剥夺了其42-aa细胞质尾部的分子。鉴于这是发现的最常见的MICA等位基因，我们开始分析细胞质尾部缺失的功能后果。在这里，我们发现MICA在人肠上皮的基底外侧表面天然表达，这是假定与上皮内T淋巴细胞和INK淋巴细胞相互作用的部位。然后，我们证明，在极化上皮细胞中，尽管全长MICA蛋白被分类到基侧膜，但细胞质尾部缺失结构以及自然存在的A5.1等位基因被异常地转运到根尖表面。定点诱变鉴定了细胞质尾部编码的亮氨酸-缬氨酸双疏水串联作为基侧分选信号。因此，MICA在上皮细胞内的生理位置是由其细胞质尾部控制的，这意味着在A5.1纯合子个体中存在损伤，可能与NK和T淋巴细胞对上皮恶性肿瘤的免疫监视有关。
The MHC class I chain-related MICA molecule is a stress-induced, highly polymorphic, epithelia-specific, membrane-bound glycoprotein interacting with the activating NK cell receptor NKG2D and/or gut-enriched Vdelta1-bearing gammadelta T cells. We have previously reported the presence of a MICA transmembrane-encoded short-tandem repeat harboring a peculiar allele, A5.1, characterized by a frame shift mutation leading to a premature intradomain stop codon, thus denying the molecule of its 42-aa cytoplasmic tail. Given that this is the most common population-wide MICA allele found, we set out to analyze the functional consequences of cytoplasmic tail deletion. Here, we show native expression of MICA at the basolateral surface of human intestinal epithelium, the site of putative interaction with intraepithelial T and INK lymphocytes. We then demonstrate, in polarized epithelial cells, that although the full-length MICA protein is sorted to the basolateral membrane, the cytoplasmic tail-deleted construct as well as the naturally occurring A5.1 allele are aberrantly transported to the apical surface. Site-directed mutagenesis identified the cytoplasmic tail-encoded leucine-valine dihydrophobic tandem as the basolateral sorting signal. Hence, the physiological location of MICA within epithelial cells is governed by its cytoplasmic tail, implying impairment in A5.1 homozygous individuals, perhaps relevant to the immunological surveillance exerted by NK and T lymphocytes on epithelial malignancies.