Comparison of the Intracellular Trafficking Itinerary of CTLA-4 Orthologues
Comparison of the Intracellular Trafficking Itinerary of CTLA-4 Orthologues
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DOI：
10.1371/journal.pone.0060903
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发表时间：
2013-04-02
期刊：
影响因子：
3.7
通讯作者：
Sansom, David M.
中科院分区：
文献类型：
--
作者：
Kaur, Satdip;Qureshi, Omar S.;Sansom, David M.
CTLA-4是T细胞免疫应答的重要抑制剂。在稳态下，大多数CTLA-4由于通过胞质结构域内基于酪氨酸的内吞基序（YVKM）介导的组成性内化而驻留在细胞内区室中。该结构域在哺乳动物中高度保守，表明强烈的选择压力。相反，C-末端结构域在非哺乳动物如鱼、爪蟾和鸟类中变化很大。我们比较了这些物种的C-末端与人CTLA-4直接运输CTLA-4的能力。使用嵌合的方法，内吞作用被认为是保守的人，非洲爪蟾和鸡CTLA-4，但大幅减少鳟鱼CTLA-4，缺乏保守的YXXM基序。然而，我们确定了一个替代YXXF基序鳟鱼CTLA-4，允许有限的内吞作用。内化后，CTLA-4被再循环或靶向降解。人和鸡的CTLA-4，其中包含一个YVKM基序，显示出有效的回收相比，非洲爪蟾CTLA-4，其中包含一个效率较低的YEKM基序。人CTLA-4中该基序的特异性突变减少了受体再循环。这些发现表明CTLA-4的内吞和再循环潜力的进化发展，这可能有助于CTLA-4在哺乳动物免疫系统中的更精细功能。
CTLA-4 is an essential inhibitor of T cell immune responses. At steady state, most CTLA-4 resides in intracellular compartments due to constitutive internalisation mediated via a tyrosine based endocytic motif (YVKM) within the cytoplasmic domain. This domain is highly conserved in mammals suggesting strong selective pressure. In contrast, the C-terminal domain varies considerably in non-mammals such as fish, xenopus and birds. We compared the ability of the C-terminus of these species to direct the trafficking of CTLA-4 with human CTLA-4. Using a chimeric approach, endocytosis was found to be conserved between human, xenopus and chicken CTLA-4 but was reduced substantially in trout CTLA-4, which lacks the conserved YXXM motif. Nevertheless, we identified an alternative YXXF motif in trout CTLA-4 that permitted limited endocytosis. Post-internalisation, CTLA-4 was either recycled or targeted for degradation. Human and chicken CTLA-4, which contain a YVKM motif, showed efficient recycling compared to xenopus CTLA-4 which contains a less efficient YEKM motif. Specific mutation of this motif in human CTLA-4 reduced receptor recycling. These findings suggest evolutionary development in the endocytic and recycling potential of CTLA-4, which may facilitate more refined functions of CTLA-4 within the mammalian immune system.