A basolateral sorting motif in the MICA cytoplasmic tail

被引:106
作者
Suemizu, H
Radosavljevic, M
Kimura, M
Sadahiro, S
Yoshimura, S
Bahram, S
Inoko, H
机构
[1] INSERM, Ctr Rech Immunol & Hematol, Contrat Rech Strateg, F-67085 Strasbourg, France
[2] Tokai Univ, Sch Med, Dept Genet Informat, Isehara, Kanagawa 2591193, Japan
[3] Tokai Univ, Sch Med, Dept Surg, Isehara, Kanagawa 2591193, Japan
[4] Ctr Inst Expt Anim, Kawasaki, Kanagawa 2160001, Japan
关键词
D O I
10.1073/pnas.052701099
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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收藏
页码:2971 / 2976
页数:6
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