An antigenic peptide produced by reverse splicing and double asparagine deamidation
An antigenic peptide produced by reverse splicing and double asparagine deamidation
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DOI：
10.1073/pnas.1101892108
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发表时间：
2011-07-19
影响因子：
11.1
通讯作者：
Van den Eynde, Benoit J.
中科院分区：
文献类型：
--
作者：
Dalet, Alexandre;Robbins, Paul F.;Van den Eynde, Benoit J.
多种非常规的翻译和翻译后机制有助于抗原肽的产生，从而增加了由MHC I类分子呈递的肽库的多样性。在这里，我们描述了一个I类限制性肽，结合几个翻译后修饰。它来源于酪氨酸酶，并被从黑素瘤患者分离的肿瘤浸润淋巴细胞识别。这种不寻常的抗原肽是由两个不连续的酪氨酸酶片段以相反的顺序拼接在一起。此外，它含有两个天冬氨酸残基，取代酪氨酸酶序列中编码的天冬酰胺。我们证实，这种肽是自然呈现在黑色素瘤细胞的表面，我们表明，它的加工顺序需要翻译的酪氨酸酶进入内质网和它的retrotranslocation到胞质溶胶，在那里的两个天冬酰胺的肽-N-聚糖酶的去糖基化，把它们变成通过脱酰胺化的arbitrate。该过程之后是通过标准蛋白酶体切割和剪接适当的片段，并通过与抗原加工相关的转运蛋白（TAP）将所得肽额外转运到内质网中。
A variety of unconventional translational and posttranslational mechanisms contribute to the production of antigenic peptides, thereby increasing the diversity of the peptide repertoire presented by MHC class I molecules. Here, we describe a class I-restricted peptide that combines several posttranslational modifications. It is derived from tyrosinase and recognized by tumor-infiltrating lymphocytes isolated from a melanoma patient. This unusual antigenic peptide is made of two noncontiguous tyrosinase fragments that are spliced together in the reverse order. In addition, it contains two aspartate residues that replace the asparagines encoded in the tyrosinase sequence. We confirmed that this peptide is naturally presented at the surface of melanoma cells, and we showed that its processing sequentially requires translation of tyrosinase into the endoplasmic reticulum and its retrotranslocation into the cytosol, where deglycosylation of the two asparagines by peptide-N-glycanase turns them into aspartates by deamidation. This process is followed by cleavage and splicing of the appropriate fragments by the standard proteasome and additional transport of the resulting peptide into the endoplasmic reticulum through the transporter associated with antigen processing (TAP).