Tryptophan depletion results in tryptophan-to-phenylalanine substitutants.

Details

Serval ID
serval:BIB_ED604B40AD79
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Tryptophan depletion results in tryptophan-to-phenylalanine substitutants.
Journal
Nature
Author(s)
Pataskar A., Champagne J., Nagel R., Kenski J., Laos M., Michaux J., Pak H.S., Bleijerveld O.B., Mordente K., Navarro J.M., Blommaert N., Nielsen M.M., Lovecchio D., Stone E., Georgiou G., de Gooijer M.C., van Tellingen O., Altelaar M., Joosten R.P., Perrakis A., Olweus J., Bassani-Sternberg M., Peeper D.S., Agami R.
ISSN
1476-4687 (Electronic)
ISSN-L
0028-0836
Publication state
Published
Issued date
03/2022
Peer-reviewed
Oui
Volume
603
Number
7902
Pages
721-727
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Activated T cells secrete interferon-γ, which triggers intracellular tryptophan shortage by upregulating the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme <sup>1-4</sup> . 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.
Pubmed
Web of science
Open Access
Yes
Create date
21/03/2022 10:32
Last modification date
15/07/2022 6:36
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