In:
Nature, Springer Science and Business Media LLC, Vol. 603, No. 7902 ( 2022-03-24), p. 721-727
Abstract:
Activated T cells secrete interferon-γ, which triggers intracellular tryptophan shortage by upregulating the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme 1–4 . 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.
Type of Medium:
Online Resource
ISSN:
0028-0836
,
1476-4687
DOI:
10.1038/s41586-022-04499-2
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2022
detail.hit.zdb_id:
120714-3
detail.hit.zdb_id:
1413423-8
SSG:
11
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