Translation from the 5' untranslated region shapes the integrated stress response.
Translation from the 5' untranslated region shapes the integrated stress response.
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DOI：
10.1126/science.aad3867
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发表时间：
2016-01-29
期刊：
影响因子：
--
通讯作者：
Walter P
中科院分区：
文献类型：
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作者：
Starck SR;Tsai JC;Chen K;Shodiya M;Wang L;Yahiro K;Martins-Green M;Shastri N;Walter P
不同于带注释的编码序列的翻译区域已成为蛋白质组的基本要素。这包括存在于由综合应激反应（ISR）控制的mrna中的上游开放阅读框（uorf），尽管真核起始因子2 -鸟苷三磷酸-引发剂甲硫基转移RNA （eIF2·GTP·Met-tRNAiMet）受到抑制，但它们仍显示出“特权”翻译。我们开发了T细胞的追踪翻译，以直接测量ISR过程中uorf的翻译产物。我们在结合免疫球蛋白蛋白（BiP） mRNA（也称为热休克70千尔顿蛋白5mRNA）的5 '非翻译区发现了uorf的标志性翻译事件，这些事件不是在起始密码子aug启动的。在ISR期间，BiP的表达既需要替代启动因子eIF2A，也需要非aug启动的uorf。我们提出，对于各种伴侣蛋白，持续的uORF翻译可以从ISR中屏蔽选择的mrna，同时产生可以作为主要组织相容性复合体I类配体的肽，标记细胞以供适应性免疫系统识别。
Translated regions distinct from annotated coding sequences have emerged as essential elements of the proteome. This includes upstream open reading frames (uORFs) present in mRNAs controlled by the integrated stress response (ISR) that show “privileged” translation despite inhibited eukaryotic initiation factor 2–guanosine triphosphate–initiator methionyl transfer RNA (eIF2·GTP·Met-tRNAiMet). We developed tracing translation by T cells to directly measure the translation products of uORFs during the ISR. We identified signature translation events from uORFs in the 5′ untranslated region of binding immunoglobulin protein (BiP) mRNA (also called heat shock 70-kilodalton protein 5mRNA) that were not initiated at the start codon AUG. BiP expression during the ISR required both the alternative initiation factor eIF2A and non–AUG-initiated uORFs. We propose that persistent uORF translation, for a variety of chaperones, shelters select mRNAs from the ISR, while simultaneously generating peptides that could serve as major histocompatibility complex class I ligands, marking cells for recognition by the adaptive immune system.