PXD028921-1

PXD028921 is an original dataset announced via ProteomeXchange.

Title	Tryptophan depletion provokes the production and presentation of in-frame tryptophan to phenylalanine substitutions
Description	Activated 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.
HostingRepository	PRIDE
AnnounceDate	2021-12-23
AnnouncementXML	Submission_2021-12-23_05:52:00.576.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Onno Bleijerveld
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2021-10-04 10:01:07	ID requested
⏵ 1	2021-12-23 05:52:00	announced
2	2022-03-25 08:54:20	announced	2022-03-25: Updated publication reference for PubMed record(s): 35264796.

Dataset with its publication pending

submitter keyword: tryptophan depletion, amino acid substitution, LC-MS/MS, cancer

Reuven Agami
contact affiliation	Division of Oncogenomics, Oncode institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, the Netherlands
contact email	r.agami@nki.nl
lab head
Onno Bleijerveld
contact affiliation	The Netherlands Cancer Institute
contact email	o.bleijerveld@nki.nl
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD028921
     1. Label: PRIDE project
     2. Name: Tryptophan depletion provokes the production and presentation of in-frame tryptophan to phenylalanine substitutions