{"doi":"10.1038/s41586-022-04499-2","title":"Tryptophan depletion results in tryptophan-to-phenylalanine substitutants","abstract":". Here we show that despite tryptophan depletion, in-frame protein synthesis continues across tryptophan codons. We identified tryptophan-to-phenylalanine codon reassignment (W>F) as the major event facilitating this process, and pinpointed tryptophanyl-tRNA synthetase (WARS1) as its source. We call these W>F peptides 'substitutants' to distinguish them from genetically encoded mutants. Using large-scale proteomics analyses, we demonstrate W>F substitutants to be highly abundant in multiple cancer types. W>F substitutants were enriched in tumours relative to matching adjacent normal tissues, and were associated with increased IDO1 expression, oncogenic signalling and the tumour-immune microenvironment. Functionally, W>F substitutants can impair protein activity, but also expand the landscape of antigens presented at the cell surface to activate T cell responses. Thus, substitutants are generated by an alternative decoding mechanism with potential effects on gene function and tumour immunoreactivity.","journal":"Nature","year":2022,"id":233231,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":138,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9586,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":846047,"name":"Julien Champagne","orcid":"0000-0001-8460-858X","position":1,"is_corresponding":false},{"id":847091,"name":"Remco Nagel","orcid":null,"position":2,"is_corresponding":false},{"id":846048,"name":"Juliana C.N. Kenski","orcid":"0009-0003-1558-8388","position":3,"is_corresponding":false},{"id":847092,"name":"Maarja Laos","orcid":null,"position":4,"is_corresponding":false},{"id":586121,"name":"Justine Michaux","orcid":"0009-0006-3128-2436","position":5,"is_corresponding":false},{"id":847093,"name":"Hui Song Pak","orcid":null,"position":6,"is_corresponding":false},{"id":846049,"name":"Onno B. Bleijerveld","orcid":"0000-0002-9395-2347","position":7,"is_corresponding":false},{"id":847094,"name":"Kelly Mordente","orcid":null,"position":8,"is_corresponding":false},{"id":846050,"name":"Jasmine Montenegro Navarro","orcid":"0000-0001-5644-7758","position":9,"is_corresponding":false},{"id":847095,"name":"Naomi Blommaert","orcid":null,"position":10,"is_corresponding":false},{"id":228586,"name":"Morten M. Nielsen","orcid":"0000-0001-5432-2396","position":11,"is_corresponding":false},{"id":846051,"name":"Domenica Lovecchio","orcid":"0000-0002-6297-8384","position":12,"is_corresponding":false},{"id":106347,"name":"Everett Stone","orcid":"0000-0002-2459-9762","position":13,"is_corresponding":false},{"id":106348,"name":"George Georgiou","orcid":"0000-0002-8823-3073","position":14,"is_corresponding":false},{"id":846052,"name":"Mark C. de Gooijer","orcid":"0000-0002-2812-991X","position":15,"is_corresponding":false},{"id":846053,"name":"Olaf van Tellingen","orcid":"0000-0002-1037-6269","position":16,"is_corresponding":false},{"id":350263,"name":"Maarten Altelaar","orcid":"0000-0001-5093-5945","position":17,"is_corresponding":false},{"id":117600,"name":"Robbie P. Joosten","orcid":"0000-0002-2323-2686","position":18,"is_corresponding":false},{"id":117601,"name":"Anastassis Perrakis","orcid":"0000-0002-1151-6227","position":19,"is_corresponding":false},{"id":673478,"name":"Johanna Olweus","orcid":"0000-0002-1898-3100","position":20,"is_corresponding":false},{"id":17790,"name":"Michal Bassani-Sternberg","orcid":"0000-0002-1934-954X","position":21,"is_corresponding":false},{"id":30181,"name":"Daniel S. Peeper","orcid":"0000-0003-1293-3177","position":22,"is_corresponding":false},{"id":846054,"name":"Reuven Agami","orcid":"0000-0002-2848-2473","position":23,"is_corresponding":false},{"id":846046,"name":"Abhijeet Pataskar","orcid":"0000-0003-1537-3371","position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":null,"created_at":"2026-07-19T00:21:25.223756Z","pmid":"35264796","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}