In vivo genetic mutations define predominant functions of the human T-cell leukemia/lymphoma virus p12I protein
In vivo genetic mutations define predominant functions of the human T-cell leukemia/lymphoma virus p12I protein
复制标题
DOI：
10.1182/blood-2008-04-146928
复制
发表时间：
2009-04-16
期刊：
影响因子：
20.3
通讯作者：
Franchini, Genoveffa
中科院分区：
文献类型：
--
作者：
Fukumoto, Risaku;Andresen, Vibeke;Franchini, Genoveffa
人类 T 细胞白血病/淋巴瘤病毒 1 型 (HTLV-1) ORF-I 编码 99 个氨基酸的疏水膜蛋白 p12(I)，它影响不同细胞区室中的受体。我们在此报告蛋白水解切割决定了 p12(I) 的不同细胞定位和功能。去除 p12(I) 氨基末端内的非规范内质网 (ER) 保留/检索信号对于运输至高尔基体和生成完全切割的 8-kDa 蛋白质是必要的。 8 kDa 蛋白依次运输至细胞表面，在 T 细胞受体 (TCR) 连接后被募集至免疫突触，并下调 TCR 近端信号传导。未切割的 12-kDa 形式的 p12(I) 存在于 ER 中，并与白细胞介素 2 受体 (IL-2R) 的 β 链和 γ(c) 链、主要组织相容性复合物 (MHC) I 类的重链以及钙网蛋白和钙连接蛋白相互作用。对 HTLV-1 感染患者离体样本的 ORF-I 进行遗传分析，揭示了 ORF-I 内影响蛋白水解切割的主要氨基酸取代，表明 p12(I) 的 ER 相关功能可能有助于宿主中受感染 T 细胞的存活和增殖。 （血。2009；113：3726-3734）
The human T-cell leukemia/lymphoma virus type 1 (HTLV-1) ORF-I encodes a 99-amino acid hydrophobic membrane protein, p12(I), that affects receptors in different cellular compartments. We report here that proteolytic cleavage dictates different cellular localization and functions of p12(I). The removal of a noncanonical endoplasmic reticulum (ER) retention/retrieval signal within the amino terminus of p12(I) is necessary for trafficking to the Golgi apparatus and generation of a completely cleaved 8-kDa protein. The 8-kDa protein in turn traffics to the cell surface, is recruited to the immunologic synapse following T-cell receptor (TCR) ligation, and down-regulates TCR proximal signaling. The uncleaved 12-kDa form of p12(I) resides in the ER and interacts with the beta and gamma(c) chains of the interleukin-2 receptor (IL-2R), the heavy chain of the major histocompatibility complex (MHC) class I, as well as calreticulin and calnexin. Genetic analysis of ORF-I from ex vivo samples of HTLV-1-infected patients reveals predominant amino acid substitutions within ORF-I that affect proteolytic cleavage, suggesting that ER-associated functions of p12(I) may contribute to the survival and proliferation of the infected T cells in the host. (Blood. 2009; 113: 3726-3734)