Oncogene-dependent sloppiness in mRNA translation

Champagne, Julien; Pataskar, Abhijeet; Blommaert, Naomi; Nagel, Remco; Wernaart, Demi; Ramalho, Sofia; Kenski, Juliana C.N.; Bleijerveld, Onno B.; Zaal, Esther A.; Berkers, Celia R.; Altelaar, Maarten; Peeper, Daniel S.; Faller, William J.; Agami, Reuven

doi:10.1016/j.molcel.2021.09.002

Cited by 38 publications

(37 citation statements)

References 72 publications

(88 reference statements)

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“…We then searched for control out-of-frame tGFP peptides and for all possible codon reassignment and translational bypass events that may arise at codon W93. We confirmed the presence of tGFP peptides originating from frameshift events following IFNγ treatment, but detected no translational bypass events 6 , 8 (Fig. 1b , Extended Data Fig.…”

Section: Codon Reassignment By Tryptophan Depletionsupporting

confidence: 64%

“…Measurement of H2-Kb-bound SIINFEKL levels. MD55A3 and HT29 cells were transduced with lentiviruses produced from pCDH-Hygro-H2-Kb and selected with hygromycin (Invitrogen) 8 . Next, the H2-Kb expressing cells were transduced with lentiviruses generated from the pCDH-V5-ATF4 1-63/W93Y -tGFP-SIINFEKL or the mutant versions thereof.…”

Section: Fluorescence-activated Cell Sortingmentioning

confidence: 99%

“…IFNγ also stimulates T cell activity by upregulating human leukocyte antigen (HLA) levels at the cell surface 5 and increases the repertoire of epitopes by producing aberrant frameshifted proteins through intracellular IDO1-mediated tryptophan depletion 6 . In addition to frameshifting ribosomes [6][7][8] , amino acid shortages can elicit codon reassignments in bacteria and yeast, thereby altering the decoding of a codon irrespective of its mRNA context to promote in-frame protein synthesis [9][10][11] . Additionally, codon reassignment due to alternative tRNA aminoacylation has been observed in yeast, where the CUG codon is decoded as both serine and leucine 12 .…”

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confidence: 99%

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Tryptophan depletion results in tryptophan-to-phenylalanine substitutants

Pataskar

Champagne

Nagel

et al. 2022

Nature

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

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Section: Codon Reassignment By Tryptophan Depletionsupporting

confidence: 64%

Section: Fluorescence-activated Cell Sortingmentioning

confidence: 99%

mentioning

confidence: 99%

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Tryptophan depletion results in tryptophan-to-phenylalanine substitutants

Pataskar

Champagne

Nagel

et al. 2022

Nature

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“…Compared with cystine and leucine, aberrant tryptophan metabolisms disturb immune responses through more diverse pathways. Deficiency of tryptophan in melanoma cells is found to disturb mRNA translation through ribosomal frameshifting, which results in the presentation of aberrant trans-frame peptides, hence exposing melanoma cells to immune cells ( 118 , 119 ). Interestingly, this tryptophan depletion in melanoma cells is largely due to RAS activation and could be reversed by pharmacological inhibition of the MAPK pathway, showing that oncogenes somehow paradoxically regulate the immunogenicity of tumor cells via the regulation of amino acid metabolism ( 119 ).…”

Section: The Role Of Amino Acid Metabolism In Melanoma Immunologymentioning

confidence: 99%

“…Deficiency of tryptophan in melanoma cells is found to disturb mRNA translation through ribosomal frameshifting, which results in the presentation of aberrant trans-frame peptides, hence exposing melanoma cells to immune cells ( 118 , 119 ). Interestingly, this tryptophan depletion in melanoma cells is largely due to RAS activation and could be reversed by pharmacological inhibition of the MAPK pathway, showing that oncogenes somehow paradoxically regulate the immunogenicity of tumor cells via the regulation of amino acid metabolism ( 119 ). Aside from the influence on the immunological alterations of tumor cells, the abnormally activated indoleamine 2,3-dioxygenase (IDO1)/tryptophan 2,3-dioxygenase (TDO) pathway of tryptophan metabolism alters the immune profile of TME, which is highly related to an unoptimistic prognosis of patients with melanoma.…”

Section: The Role Of Amino Acid Metabolism In Melanoma Immunologymentioning

confidence: 99%

Metabolic rewiring directs melanoma immunology

et al. 2022

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Melanoma results from the malignant transformation of melanocytes and accounts for the most lethal type of skin cancers. In the pathogenesis of melanoma, disordered metabolism is a hallmark characteristic with multiple metabolic paradigms involved in, e.g., glycolysis, lipid metabolism, amino acid metabolism, oxidative phosphorylation, and autophagy. Under the driving forces of oncogenic mutations, melanoma metabolism is rewired to provide not only building bricks for macromolecule synthesis and sufficient energy for rapid proliferation and metastasis but also various metabolic intermediates for signal pathway transduction. Of note, metabolic alterations in tumor orchestrate tumor immunology by affecting the functions of surrounding immune cells, thereby interfering with their antitumor capacity, in addition to the direct influence on tumor cell intrinsic biological activities. In this review, we first introduced the epidemiology, clinical characteristics, and treatment proceedings of melanoma. Then, the components of the tumor microenvironment, especially different populations of immune cells and their roles in antitumor immunity, were reviewed. Sequentially, how metabolic rewiring contributes to tumor cell malignant behaviors in melanoma pathogenesis was discussed. Following this, the proceedings of metabolism- and metabolic intermediate-regulated tumor immunology were comprehensively dissertated. Finally, we summarized currently available drugs that can be employed to target metabolism to intervene tumor immunology and modulate immunotherapy.

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Hyperactivation of mTOR/eIF4E Signaling Pathway Promotes the Production of Tryptophan‐To‐Phenylalanine Substitutants in EBV‐Positive Gastric Cancer

Zheng,

Zhong,

Wei

et al. 2024

Advanced Science

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Although messenger RNA translation is tightly regulated to preserve protein synthesis and cellular homeostasis, chronic exposure to interferon‐γ (IFN‐γ) in several cancers can lead to tryptophan (Trp) shortage via the indoleamine‐2,3‐dioxygenase (IDO)‐ kynurenine pathway and therefore promotes the production of aberrant peptides by ribosomal frameshifting and tryptophan‐to‐phenylalanine (W>F) codon reassignment events (substitutants) specifically at Trp codons. However, the effect of Trp depletion on the generation of aberrant peptides by ribosomal mistranslation in gastric cancer (GC) is still obscure. Here, it is shows that the abundant infiltrating lymphocytes in EBV‐positive GC continuously secreted IFN‐γ, upregulated IDO1 expression, leading to Trp shortage and the induction of W>F substitutants. Intriguingly, the production of W>F substitutants in EBV‐positive GC is linked to antigen presentation and the activation of the mTOR/eIF4E signaling pathway. Inhibiting either the mTOR/eIF4E pathway or EIF4E expression counteracted the production and antigen presentation of W>F substitutants. Thus, the mTOR/eIF4E pathway exposed the vulnerability of gastric cancer by accelerating the production of aberrant peptides and boosting immune activation through W>F substitutant events. This work proposes that EBV‐positive GC patients with mTOR/eIF4E hyperactivation may benefit from anti‐tumor immunotherapy.

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Oncogene-dependent sloppiness in mRNA translation

Abstract: Highlights d Sloppiness is defined by ribosomal frameshifting upon tryptophan shortage d MAPK pathway hyperactivation links sloppiness to cancer d Sloppiness causes aberrant peptide presentation at the cell surface d Drug-resistant cancer cells remain sloppy and are targeted by T cells

Cited by 38 publications

References 72 publications

Tryptophan depletion results in tryptophan-to-phenylalanine substitutants

Tryptophan depletion results in tryptophan-to-phenylalanine substitutants

Metabolic rewiring directs melanoma immunology

Hyperactivation of mTOR/eIF4E Signaling Pathway Promotes the Production of Tryptophan‐To‐Phenylalanine Substitutants in EBV‐Positive Gastric Cancer

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