Tryptophan depletion results in tryptophan-to-phenylalanine substitutants

Abhijeet Pataskar, Julien Champagne, Remco Nagel, Juliana Kenski, Maarja Laos, Justine Michaux, Hui Song Pak, Onno B. Bleijerveld, Kelly Mordente, Jasmine Montenegro Navarro, Naomi Blommaert, Morten M. Nielsen, Domenica Lovecchio, Everett Stone, George Georgiou, Mark C. Gooijer, Olaf Tellingen, Maarten Altelaar, Robbie P. Joosten, Anastassis Perrakis, Johanna Olweus, Michal Bassani-Sternberg, Daniel S. Peeper and Reuven Agami ()
Additional contact information
Abhijeet Pataskar: The Netherlands Cancer Institute
Julien Champagne: The Netherlands Cancer Institute
Remco Nagel: The Netherlands Cancer Institute
Juliana Kenski: The Netherlands Cancer Institute
Maarja Laos: Oslo University Hospital Radiumhospitalet
Justine Michaux: Lausanne University Hospital (CHUV) and University of Lausanne (UNIL)
Hui Song Pak: Lausanne University Hospital (CHUV) and University of Lausanne (UNIL)
Onno B. Bleijerveld: NKI Proteomics facility, The Netherlands Cancer Institute
Kelly Mordente: The Netherlands Cancer Institute
Jasmine Montenegro Navarro: The Netherlands Cancer Institute
Naomi Blommaert: The Netherlands Cancer Institute
Morten M. Nielsen: Oslo University Hospital Radiumhospitalet
Domenica Lovecchio: The Netherlands Cancer Institute
Everett Stone: University of Texas
George Georgiou: University of Texas
Mark C. Gooijer: The Netherlands Cancer Institute
Olaf Tellingen: The Netherlands Cancer Institute
Maarten Altelaar: NKI Proteomics facility, The Netherlands Cancer Institute
Robbie P. Joosten: The Netherlands Cancer Institute
Anastassis Perrakis: The Netherlands Cancer Institute
Johanna Olweus: Oslo University Hospital Radiumhospitalet
Michal Bassani-Sternberg: Lausanne University Hospital (CHUV) and University of Lausanne (UNIL)
Daniel S. Peeper: The Netherlands Cancer Institute
Reuven Agami: The Netherlands Cancer Institute

Nature, 2022, vol. 603, issue 7902, 721-727

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41586-022-04499-2

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