The human Ly-49L gene
The human Ly-49L gene
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DOI：
10.1007/s002510050675
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发表时间：
1999-07-01
期刊：
影响因子：
3.2
通讯作者：
Trowsdale, J
中科院分区：
文献类型：
--
作者：
Barten, R;Trowsdale, J
人类 NK 细胞表达属于 Ig (KIR) 和凝集素 (CD94/NKG2) 超家族的杀伤抑制受体，而迄今为止的证据表明啮齿动物仅使用凝集素样分子。啮齿类动物有超过 9 个与 Ly-49 位点相关的凝集素基因家族。迄今为止，在人类中仅鉴定出一种 Ly-49 相关序列，即 cDNA 克隆（Westgaard 等，1998）。在本文中，我们探讨了人类 Ly-49L 基因的基因组组织。该基因显示出与小鼠相似的遗传组织。然而，外显子 5 继续通过剪接点进入下游内含子，并遇到过早终止密码子。两个等位基因被部分测序。两个序列的变异在不同个体的基因组和 cDNA 中得到证实，表明多态性水平较低。尽管基因组 Southern 印迹分析表明人类基因组中存在其他 Ly-49 相关序列，但这些序列不在 Ly-49L 基因座的 130 KB 范围内。自然杀伤 (NK) 细胞在先天免疫反应中发挥着重要作用，既可作为效应细胞杀死病原体感染的细胞，又可作为调节免疫系统先天和适应性臂其他细胞类型的细胞因子来源。在人类中，特征最明确的 NK 受体是白细胞受体复合物中第 19 号染色体 (Chr) 上编码的免疫球蛋白超家族的成员（Suto 等人，1998 年；Wagtmann 等人，1997 年）。杀伤细胞抑制受体 (KIR) 的特点是其胞质尾部有一个免疫受体酪氨酸抑制基序 (ITIM)，而杀伤细胞激活受体 (KAR) 则与一个信号转接器（即称为 DAP12 的跨膜分子）相关联（Campbell 等人，1998 年；Lanier 等人，1998 年）。除了远缘相关的 gp49B1 位点外，在小鼠系统中尚未发现直接的 KIR 或 KAR 直向同源物（Wang 等人，1997）。相反，MHC I 类分子被啮齿类动物 C 型凝集素超家族的 NK 受体识别（Brown 等人，1997b；Hoglund 等人，1997；Raulet 等人，1997）。 Ly-49 受体是 II 型跨膜蛋白的二硫键连接的同二聚体。羧基末端序列与碳水化合物识别域 (CRD) 相似。碳水化合物在识别 H2 同质异形体中的重要性尚未完全解决（Brennan 等人，1995 年；Lian 等人，1998 年；Matsumoto 等人，1998 年）。与 KIR/KAR 一样，Ly-49 家族的一些成员通过其细胞质尾部的 ITIM 基序参与负信号传导，而其他激活成员则与小鼠 DAP12 直向同源物相互作用（Mason 等人，1998 年；Smith 等人，1998 年）。 Ly-49 基因位于小鼠 Chr6 上自然杀伤基因复合体 (NKC) 的两个簇中（Brown 等人，1997a；McQueen 等人，1998）。该区域还编码 C 型凝集素超家族的其他成员，包括 CD94 和 NKG2 家族、NKRP1 和 CD69（Brown 等人，1997a；Vance 等人，1997）。基因的顺序在小鼠、大鼠和人类中是保守的。有趣的是，对小鼠痘病毒（Ectromelia）和巨细胞病毒（mCMV）的抵抗力已被定位到该区域（Depatie 等人，1997 年；Forbes 等人，1997 年）。在人类中，NKC 位于 Chr 12 短臂的同线性区域，该区域还包含 CD94/NKG2、NKRP1 和 CD69 的基因（Brown 等人，1997b；Plougastel 和 Trowsdale，1998）。我们首先在人类表达标签 (EST) 数据库中搜索啮齿动物 Ly-49 基因的人类同源物。鉴定出与大鼠 Ly-49（登录号 AA464841）的 3' 端相似的序列。从人类 RCP1 文库中分离出三个 PAC，从 LL12NCOI Chr 中分离出三个粘粒……
Human NK cells express killer inhibitory receptors belonging to the Ig (KIR) and lectin (CD94/NKG2) superfamilies, whereas on evidence to date rodents use only the lectin-like molecules. Rodents have a family of over nine lectin genes related to theLy-49 locus. So far, only one Ly-49-related sequence has been identified in human, as a cDNA clone (Westgaard et al. 1998). In this paper we explore the genomic organization of the human Ly-49L gene. The gene shows a genetic organization similar to that of the mouse. However, exon 5 continues over a splice junction into the downstream intron and runs into a premature stop codon. Two alleles were partially sequenced. Variation in the two sequences was confirmed in genomic and cDNA from different individuals, indicating a low level of polymorphism. Although genomic Southern blot analysis suggested the presence of additional Ly-49-related sequences in the human genome, these were not within 130 kilobases (kb) of the Ly-49L locus. Natural killer (NK) cells are of importance in the innate immune response both as effectors, for killing pathogen infected cells, and as a source of cytokines regulating other cell types both of the innate and adaptive arm of the immune system. In humans, the best characterized NK receptors are members of the immunoglobulin superfamily encoded on Chromosome (Chr) 19, in the leukocyte receptor complex (Suto et al. 1998; Wagtmann et al. 1997). The killer cell inhibitory receptors (KIR) are characterized by an immunoreceptor tyrosine inhibition motif (ITIM) in their cytoplasmic tail, whereas the killer cell-activating receptors (KAR) associate with a signaling adaptor, namely a transmembrane molecule called DAP12 (Campbell et al. 1998; Lanier et al. 1998). No direct KIR or KAR orthologues have been found in the murine system except for the distantly related gp49B1 locus (Wang et al. 1997). Instead, MHC class I molecules are recognized by NK receptors of the C-type lectin superfamily in rodents (Brown et al. 1997b; Hoglund et al. 1997; Raulet et al. 1997). Ly-49 receptors are disulfide linked homodimers of type II transmembrane proteins. The carboxyl-terminal sequence exhibits similarity to a carbohydrate recognition domain (CRD). The importance of carbohydrates in recognition of the H2 allomorphs is not completely resolved (Brennan et al. 1995; Lian et al. 1998; Matsumoto et al. 1998). Like KIRs/KARs, some members of the Ly-49 family are involved in negative signaling via ITIM motifs in their cytoplasmic tails, whereas other, activating, members interact with the mouse DAP12 orthologue (Mason et al. 1998; Smith et al. 1998). The Ly-49 genes are located in two clusters in the natural killer gene complex (NKC) on mouse Chr6 (Brown et al. 1997a; McQueen et al. 1998). This region also encodes other members of the C-type lectin superfamily including CD94 and the NKG2 family, NKRP1 and CD69 (Brown et al. 1997a; Vance et al. 1997). The order of the genes is conserved in mice, rats, and humans. Interestingly, resistance to mouse pox virus (Ectromelia) and cytomegalovirus (mCMV) has been mapped to this region (Depatie et al. 1997; Forbes et al. 1997). In humans, the NKC is located in a syntenic region on the short arm of Chr 12, which also contains the genes for CD94/NKG2, NKRP1 and CD69 (Brown et al. 1997b; Plougastel and Trowsdale 1998). We first searched for a human homologue of the rodent Ly-49 genes in the human expressed tags (EST) database. A sequence was identified with similarity to the 3’end of rat Ly-49 (accession number AA464841). Three PACs were isolated from the human RCP1 library and three cosmids from the LL12NCOI Chr …