PXD043612

PXD043612 is an original dataset announced via ProteomeXchange.

Title	Arginine to Cysteine substitutants in lung cancer enhance survival to chemotherapy
Description	Tryptophan and arginine are the two most prominent restrictive amino acids linked to anti-tumor activity. For tryptophan, the induction of indoleamine 2,3-dioxygenase 1 (IDO1) by interferon-gamma (IFNg) secreted by T cells, catabolizes tryptophan to kynurenine to suppress T cell activity. For arginine, tumor cells suppress Argininosuccinate Synthase 1 (ASS1) expression to limit arginine availability for T cell activity (26560030). While tryptophan shortage induces tryptophan to phenylalanine (W>F) substitutants in the proteomes of a variety of tumor types (35264796), whether arginine shortage induces arginine substitutants is unknown. Here, we interrogated the proteomes of cancer patients for arginine substitutions and identified a strong enrichment for cysteine (R>C) specifically in lung tumors. Using a biochemical assay and mass spectrometry, we validated the induction of R>C substitutants by arginine shortage and indicated their link to intracellular high cysteine levels. In the context of lung cancer, R>C events did not overlap with R>C mutations, while a strong correlation with ferroptosis genes and with oncogenic mutations related to the Kelch-like ECH-associated protein 1 (KEAP1) ferroptosis pathway was observed. Indeed, KEAP1 mutations induce intracellular cysteine levels (10.7554/eLife.45572), and the expression of intact KEAP1 in KEAP1-mutated cells suppressed R>C substitutants. We further underpinned tRNA misalignment as the underlying mechanism for R>C events, and, show that boosting R>C serves to enhance resistance to chemotherapy. Thus, our work identified a novel mechanism of enriching proteomes with cysteines, which is exploited by arginine shortage in lung cancer to better endure chemotherapy stress.
HostingRepository	PRIDE
AnnounceDate	2024-06-16
AnnouncementXML	Submission_2024-06-16_05:11:06.554.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	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2023-07-07 17:41:55	ID requested
⏵ 1	2024-06-16 05:11:07	announced

10.1016/j.molcel.2024.04.012;

Yang C, Pataskar A, Feng X, Montenegro Navarro J, Paniagua I, Jacobs JJL, Zaal EA, Berkers CR, Bleijerveld OB, Agami R, Arginine deprivation enriches lung cancer proteomes with cysteine by inducing arginine-to-cysteine substitutants. Mol Cell, 84(10):1904-1916.e7(2024) [pubmed]

submitter keyword: arginine, substituants, KEAP1, lung cancer,tryptophan

Onno B Bleijerveld
contact affiliation	NKI Proteomics Facility
contact email	o.bleijerveld@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. PXD043612
     1. Label: PRIDE project
     2. Name: Arginine to Cysteine substitutants in lung cancer enhance survival to chemotherapy