Distinct modulation of cellular immunopeptidome by the allosteric regulatory site of ER aminopeptidase 1

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Unit:
Department of Chemistry
Title:
Distinct modulation of cellular immunopeptidome by the allosteric regulatory site of ER aminopeptidase 1
Languages of Item:
English
Abstract:
ER aminopeptidase 1 (ERAP1) is an ER-resident aminopeptidase that excises N-terminal residues off peptides that then bind onto Major Histocompatibility Complex I molecules (MHC-I) and indirectly modulates adaptive immune responses. ERAP1 contains an allosteric regulatory site that accommodates the C-terminus of at least some peptide substrates, raising questions about its exact influence on antigen presentation and the potential of allosteric inhibition for cancer immunotherapy. We used an inhibitor that targets this regulatory site to study its effect on the immunopeptidome of a human cancer cell line. The immunopeptidomes of allosterically inhibited and ERAP1 knockout cells contain high-affinity peptides with sequence motifs consistent with the cellular HLA class I haplotypes, but were strikingly different in peptide composition. Compared to knockout cells, allosteric inhibition did not affect the length distribution of peptides and skewed the peptide repertoire both in terms of sequence motifs and HLA allele utilization, indicating significant mechanistic differences between the two ways of disrupting ERAP1 function. These findings suggest that the regulatory site of ERAP1 plays distinct roles in antigenic peptide selection, which should be taken into consideration when designing therapeutic interventions targeting the cancer immunopeptidome.
Creation year:
2023
Authors:
Ioannis Temponeras, Martina Samiotaki, Despoina Koumantou, Martha Nikopaschou, Jonas J.W. Kuiper, George Panayotou, Efstratios Stratikos
Pages:
29
Keywords:
Aminopeptidase, Inhibitor, ERAP1, Major Histocompatibility Molecules class I, Immunopeptidome, Human Leukocyte Antigens, Allosteric, Cancer Immunotherapy, Autoimmunity
Main subject category:
Health Sciences
Project information:
Funding was provided by internal funds of the National Centre for Scientific Research “Demokritos” and by the project “The Greek Research Infrastructure for Personalised Medicine (pMedGR)” (MIS 5002802), which is implemented under the Action “Reinforcement of the Research and Innovation Infrastructure,” funded by the Operational Programme “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014–2020) and co-financed by Greece and the European Union (European Regional Development Fund). ES would like to also acknowledge support from the Harry J. Lloyd Charitable Trust. ES, JK, and MN acknowledge funding from European Commission in the context of the Marie Skłodowska-Curie Action European Training Network CAPSTONE (954992 – CAPSTONE – H2020-MSCA-ITN-2020).
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Temponeras et al 2023 PREPRINT.pdf
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