The translation of non-canonical open reading frames controls mucosal immunity

Article

关键词: MESSENGER-RNA;    PROTEIN;    SALMONELLA;    SEQUENCE;    CYCLOHEXIMIDE;    ANNOTATION;    PEPTIDES;    SUITE;   

DOI  :  10.1038/s41586-018-0794-7

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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