Abstract：
Activated T cells secrete interferon-γ, which triggers intracellular tryptophan shortage by upregulating the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme1-4. 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.
摘要：
活化的T细胞分泌干扰素-γ，通过上调吲哚胺2,3-双加氧酶1（IDO1）酶1-4引发细胞内色氨酸短缺。这里我们显示尽管色氨酸耗尽,框内蛋白质合成在色氨酸密码子中继续进行。我们确定色氨酸到苯丙氨酸的密码子重新分配（W>F）是促进这一过程的主要事件，并指出色氨酸-tRNA合成酶（WARS1）作为其来源。我们称这些W>F肽为“替代品”，以区别于遗传编码的突变体。使用大规模蛋白质组学分析，我们证明W>F代用品在多种癌症类型中是高度丰富的。相对于匹配的邻近正常组织，W>F代用品在肿瘤中富集，并与IDO1表达增加有关，致癌信号和肿瘤免疫微环境。功能上,W>F替代品会损害蛋白质活性，但也扩大了抗原的景观呈现在细胞表面激活T细胞反应。因此，替代品是通过替代解码机制产生的，对基因功能和肿瘤免疫反应性具有潜在影响。
