小柯机器人

荷兰癌症研究所Reuven Agami研究小组近日取得一项新成果。他们发现色氨酸缺失会导致苯丙氨酸取代色氨酸的替代物生成。相关论文于2022年3月9日在线发表于《自然》杂志上。

在这里，研究人员表明，尽管色氨酸耗尽缺失，但跨色氨酸密码子的框内蛋白质合成仍在继续。研究人员确定了色氨酸-苯丙氨酸密码子重分配(W>F)是促进这一过程的主要事件，并确定了色氨酰- tRNA合成酶(WARS1)是其主要的酶。他们将这些 W>F 肽称为“取代物”，以将它们与遗传编码的突变体区分开来。

使用大规模蛋白质组学分析，他们证明 W>F 取代物在多种癌症类型中非常丰富。相对于匹配的邻近正常组织，W>F 取代物在肿瘤中富集，并且与 IDO1 表达增加、致癌信号传导和肿瘤免疫微环境相关。从功能上讲，W>F取代物可以削弱蛋白质的活性，但也可以扩大抗原在细胞表面的分布以激活T细胞反应。因此，取代物是由另一种解码机制产生的，对基因功能和肿瘤免疫反应具有潜在的影响。

据介绍，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)酶来触发细胞内的色氨酸短缺。

附：英文原文

Title: Tryptophan depletion results in tryptophan-to-phenylalanine substitutants

Author: Pataskar, Abhijeet, Champagne, Julien, Nagel, Remco, Kenski, Juliana, Laos, Maarja, Michaux, Justine, Pak, Hui Song, Bleijerveld, Onno B., Mordente, Kelly, Navarro, Jasmine Montenegro, Blommaert, Naomi, Nielsen, Morten M., Lovecchio, Domenica, Stone, Everett, Georgiou, George, de Gooijer, Mark C., van Tellingen, Olaf, Altelaar, Maarten, Joosten, Robbie P., Perrakis, Anastassis, Olweus, Johanna, Bassani-Sternberg, Michal, Peeper, Daniel S., Agami, Reuven

Issue&Volume: 2022-03-09

Abstract: Activated T cells secrete interferon-γ, which triggers intracellular tryptophan shortage by upregulating the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme1,2,3,4. 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.

DOI: 10.1038/s41586-022-04499-2

Source: https://www.nature.com/articles/s41586-022-04499-2

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html