The translation of non-canonical open reading frames controls mucosal immunity
The translation of non-canonical open reading frames controls mucosal immunity
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DOI：
10.1038/s41586-018-0794-7
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发表时间：
2018-12-20
期刊：
影响因子：
64.8
通讯作者：
Flavell, Richard A.
中科院分区：
文献类型：
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作者：
Jackson, Ruaidhri;Kroehling, Lina;Flavell, Richard A.
哺乳动物蛋白质编码基因组的注释是不完整的。开放阅读框（ORF）的任意大小限制和对甲硫氨酸密码子作为翻译的唯一起始子的绝对要求限制了具有非典型蛋白质编码潜力的潜在重要转录物的鉴定（1，2）。在这里，使用无偏见的转录组学方法在巨噬细胞响应细菌感染，我们表明，核糖体与大量的RNA，以前被注释为“非蛋白质编码”。虽然这种非典型的ORF可以编码功能蛋白的想法是有争议的（3，4），我们确定了一系列短的和非ATG启动的ORF，可以产生稳定的和空间上不同的蛋白质。值得注意的是，我们表明，一个新的ORF的翻译“隐藏”在长的非编码RNA Aw112010是必不可少的编排在细菌感染和结肠炎的粘膜免疫。这项工作扩展了我们对蛋白质编码基因组的解释，并证明了从非经典ORF产生的蛋白质产物对体内免疫反应至关重要。因此，我们提出，非典型的ORF包含基因的非编码RNA的错误注释可能会掩盖许多以前未发现的蛋白质编码基因在免疫和疾病中的重要作用。
The annotation of the mammalian protein-coding genome is incomplete. Arbitrary size restriction of open reading frames (ORFs) and the absolute requirement for a methionine codon as the sole initiator of translation have constrained the identification of potentially important transcripts with non-canonical proteincoding potential(1,2). Here, using unbiased transcriptomic approaches in macrophages that respond to bacterial infection, we show that ribosomes associate with a large number of RNAs that were previously annotated as 'non-protein coding'. Although the idea that such non-canonical ORFs can encode functional proteins is controversial(3,4), we identify a range of short and non-ATG-initiated ORFs that can generate stable and spatially distinct proteins. Notably, we show that the translation of a new ORF 'hidden' within the long non-coding RNA Aw112010 is essential for the orchestration of mucosal immunity during both bacterial infection and colitis. This work expands our interpretation of the protein-coding genome and demonstrates that proteinaceous products generated from noncanonical ORFs are crucial for the immune response in vivo. We therefore propose that the misannotation of non-canonical ORFcontaining genes as non-coding RNAs may obscure the essential role of a multitude of previously undiscovered protein-coding genes in immunity and disease.