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PXD028921-2

PXD028921 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleTryptophan depletion provokes the production and presentation of in-frame tryptophan to phenylalanine substitutions
DescriptionActivated T cells secrete interferon-gamma (IFN) that triggers an intra-cellular tryptophan shortage through the activation of the Indoleamine 2,3-Dioxygenase 1 (IDO1) enzyme. Surprisingly, we here show that despite tryptophan depletion, in-frame protein synthesis bypassing tryptophan codons continues. Using mass spectrometry, we identified tryptophan to phenylalanine (W>F) substitution as the major event that facilitates in-frame protein synthesis in IFN-treated and tryptophan-depleted cells. We validated their expression using in vitro reporter assays, and pinpoint tryptophanyl-tRNA synthetase (WARS1) as the candidate gene that accounts for this event. We named these mRNA-translation-driven aberrations ‘substitutants’ to distinguish them from somatic genetic variants. To uncover their biological relevance, we interrogated cancer proteomes and phosphoproteomes of breast, lung and kidney cancers. Interestingly, we specifically identified a high level of tryptic peptides containing W>F substitutants with strong association to IDO1 expression, T cell activity, p53 mutations, and oncogenic MAPK signaling, indicating a role of infiltrating T cells in their production and highlighting cancer relevance. We further show that substitutants can impair protein function and be processed and presented at the cell surface to elicit immune cell recognition. Indeed, immunopeptidomics data from of colorectal-cancer organoids and glioblastoma cell lines revealed a large number of W>F substitutant-peptides being presented on HLA class I molecules following IFN treatment. Thus, W>F substitutants are a novel form of non-genetic mutations induced by tumor-infiltrating T cells with potential impact on gene function and on the repertoire of neopeptides presented by cancer cells.
HostingRepositoryPRIDE
AnnounceDate2021-12-23
AnnouncementXMLSubmission_2022-03-25_08:54:19.290.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterOnno Bleijerveld
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListacetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
InstrumentQ Exactive HF; Orbitrap Fusion
Dataset History
RevisionDatetimeStatusChangeLog Entry
02021-10-04 10:01:07ID requested
12021-12-23 05:52:00announced
22022-03-25 08:54:20announced2022-03-25: Updated publication reference for PubMed record(s): 35264796.
Publication List
Pataskar A, Champagne J, Nagel R, Kenski J, Laos M, Michaux J, Pak HS, Bleijerveld OB, Mordente K, Navarro JM, Blommaert N, Nielsen MM, Lovecchio D, Stone E, Georgiou G, de Gooijer MC, van Tellingen O, Altelaar M, Joosten RP, Perrakis A, Olweus J, Bassani-Sternberg M, Peeper DS, Agami R, Tryptophan depletion results in tryptophan-to-phenylalanine substitutants. Nature, 603(7902):721-727(2022) [pubmed]
Keyword List
submitter keyword: tryptophan depletion, amino acid substitution, LC-MS/MS, cancer
Contact List
Reuven Agami
contact affiliationDivision of Oncogenomics, Oncode institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, the Netherlands
contact emailr.agami@nki.nl
lab head
Onno Bleijerveld
contact affiliationThe Netherlands Cancer Institute
contact emailo.bleijerveld@nki.nl
dataset submitter
Full Dataset Link List
Dataset FTP location
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