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

• Published in: Nature (London) Vol. 564; no. 7736; pp. 434 - 438
• Main Authors: Jackson, Ruaidhrí, Kroehling, Lina, Khitun, Alexandra, Bailis, Will, Jarret, Abigail, York, Autumn G., Khan, Omair M., Brewer, J. Richard, Skadow, Mathias H., Duizer, Coco, Harman, Christian C. D., Chang, Lelina, Bielecki, Piotr, Solis, Angel G., Steach, Holly R., Slavoff, Sarah, Flavell, Richard A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2018; Nature Publishing Group
• Subjects: 38; 38/39; 38/91; 631/208/726; 631/250/347; 631/337/574; 64; 64/60; 82/58; Animals; Annotations; B cells; Bacterial diseases; Bacterial infections; Bacterial Infections - genetics; Bacterial Infections - immunology; Bacterial Infections - metabolism; Bacterial Infections - microbiology; Bioinformatics; Codons; Colitis; Colitis - genetics; Colitis - immunology; Colitis - metabolism; Gene expression; Genes; Genomes; Genomics; Humanities and Social Sciences; Immune response; Immune system; Immunity; Immunity, Mucosal - drug effects; Immunity, Mucosal - genetics; Infection; Infections; Inflammation; Inflammatory bowel disease; Interleukin-12 - biosynthesis; Letter; Lipopolysaccharides - pharmacology; Macrophages; Macrophages - immunology; Macrophages - metabolism; Methionine; Mice; Mucosal immunity; Mucous membrane; multidisciplinary; Non-coding RNA; Open reading frames; Open Reading Frames - genetics; Peptides; Physiological aspects; Protein Biosynthesis - drug effects; Protein Biosynthesis - genetics; Proteins; Resveratrol; Ribonucleic acid; Ribosomes; Ribosomes - drug effects; Ribosomes - metabolism; RNA; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Salmonella; Salmonella typhimurium - immunology; Science; Science (multidisciplinary); Transcriptome - drug effects; Transcriptome - genetics; Translation
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-018-0794-7

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 protein-coding 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 non-canonical ORFs are crucial for the immune response in vivo. We therefore propose that the misannotation of non-canonical ORF-containing genes as non-coding RNAs may obscure the essential role of a multitude of previously undiscovered protein-coding genes in immunity and disease. In mouse macrophages, a range of short and non-ATG-initiated open reading frames that can generate proteins are identified, one of which is shown to be essential for host immunity to enteric mucosal infection and inflammation.