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比较 ctla-4 同源物的细胞内运输途径。

Comparison of the intracellular trafficking itinerary of ctla-4 orthologues.

机构信息

The MRC Centre for Immune Regulation, School of Immunity and Infection, University of Birmingham Medical School, Birmingham, United Kingdom.

出版信息

PLoS One. 2013;8(4):e60903. doi: 10.1371/journal.pone.0060903. Epub 2013 Apr 2.

DOI:10.1371/journal.pone.0060903
PMID:23565286
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3614947/
Abstract

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.

摘要

细胞毒性 T 淋巴细胞相关抗原 4（CTLA-4）是 T 细胞免疫反应的重要抑制剂。在稳定状态下，由于胞质域内的酪氨酸基内吞基序（YVKM）介导的组成性内化，大多数 CTLA-4 存在于细胞内隔室中。该结构域在哺乳动物中高度保守，表明存在强烈的选择压力。相比之下，非哺乳动物（如鱼类、非洲爪蟾和鸟类）的 C 端结构域变化很大。我们比较了这些物种的 C 端在指导 CTLA-4 运输方面的能力与人类 CTLA-4 的能力。通过嵌合方法，发现人类、非洲爪蟾和鸡 CTLA-4 之间的内吞作用是保守的，但在缺乏保守的 YXXM 基序的鳟鱼 CTLA-4 中，内吞作用大大降低。然而，我们在鳟鱼 CTLA-4 中鉴定出一个替代的 YXXF 基序，该基序允许有限的内吞作用。内吞作用后，CTLA-4 要么被回收，要么被靶向降解。含有 YVKM 基序的人类和鸡 CTLA-4 与含有效率较低的 YEKM 基序的非洲爪蟾 CTLA-4 相比，具有有效的回收作用。人类 CTLA-4 中该基序的特定突变减少了受体的回收。这些发现表明 CTLA-4 的内吞作用和回收潜力在进化上得到了发展，这可能促进了 CTLA-4 在哺乳动物免疫系统中更精细的功能。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62d5/3614947/ac0241b19d85/pone.0060903.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62d5/3614947/6a12e5f4ae55/pone.0060903.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62d5/3614947/499aa2b42cb8/pone.0060903.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62d5/3614947/d99de8be863e/pone.0060903.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62d5/3614947/980774787451/pone.0060903.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62d5/3614947/b4308310cfe8/pone.0060903.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62d5/3614947/ac0241b19d85/pone.0060903.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62d5/3614947/6a12e5f4ae55/pone.0060903.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62d5/3614947/499aa2b42cb8/pone.0060903.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62d5/3614947/d99de8be863e/pone.0060903.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62d5/3614947/980774787451/pone.0060903.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62d5/3614947/b4308310cfe8/pone.0060903.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62d5/3614947/ac0241b19d85/pone.0060903.g006.jpg

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