Tryptophan depletion results in tryptophan-to-phenylalanine substitutants

Article

关键词: PROTEOGENOMIC CHARACTERIZATION;    ENRICHMENT ANALYSIS;    CELL RESPONSES;    CYSTEINE;    REVEALS;    IMMUNE;    COLI;   

DOI  :  10.1038/s41586-022-04499-2

来源: SCIE

【 摘 要 】

Activated T cells secrete interferon-gamma, which triggers intracellular tryptophan shortage by upregulating the indoleamine 2,3-dioxygenase 1(IDO1) enzyme(1-4). Here we showthat despite tryptophan depletion, in-frame protein synthesis continues across tryptophan codons. We identified tryptophan-to-phenylalanine codon reassignment (W>F) asthe 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.

【 授权许可】

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