Understanding the mechanisms of Proteasome-Mediated Peptide Splicing by Comparing Splicing Efficiency by Different Proteasome Subtypes
(2023) 5th International Caparica Conference in SPLICING 2023 — Location: Caparica, Portugal (17.July.2023)
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- Authors
Vigneron, Nathalie 
- Abstract
- Anti-tumor CD8+ T cells recognize peptides of 8-to-10 amino acids that are presented at the surface of tumors by molecules of the major histocompatibility complex I (MHC I). These peptides generally result from the degradation of cellular proteins by the proteasome, and were initially thought to solely correspond to linear fragments of proteins. Several years ago, we demonstrated that proteasome also produces antigenic peptides by peptide splicing, i.e. the splicing of two peptide fragments originally distant in the parental protein [1]. The splicing process was shown to occur in the proteasome through a transpeptidation reaction involving an acyl-enzyme intermediate. Four main subtypes of proteasomes exist [2]: the standard proteasome (SP), the immunoproteasome (IP) and intermediate proteasomes 1-2-5i (SIP) and 1i-2-5i (DIP). Here, using a TMT-based quantification approach, we studied the production of six spliced human antigenic peptides by the four proteasome subtypes. Peptides FGF-5172-176/217-220, tyrosinase368-373/336-340 and gp10040-42/47-52, were shown to be better produced by the SP than the other proteasome subtypes. On the other hand, the peptides SP110296-301/286-289, gp100195-202/191or192 and gp10047-52/40-42 are better produced by the IP and the DIP. The current model of proteasome-catalyzed peptide splicing suggests that the production of a spliced peptide depends on the abundance of the peptide splicing partners. Surprisingly, we found that despite the fact that reciprocal spliced peptides RTK_QLYPEW (gp10040-42/47-52) and QLYPEW_RTK (gp10047-52/40-42) are composed of identical splicing partners, their production varies according to the proteasome subtype, indicating that the amount of splicing partner is not the only factor driving peptide splicing. In particular, our results suggest that peptide splicing efficiency might also rely on other factors such as the affinity of the C-terminal splice reactant for the primed binding site of the catalytic subunit [3]. References [1] Vigneron, N. et al. An antigenic peptide produced by peptide splicing in the proteasome. Science, 2004, 304, 587-90, https://doi.org/10.1126/science.1095522. [2] Guillaume, B et al. Two abundant proteasome subtypes that uniquely process some antigens presented by HLA class I molecules. PNAS, 2010, 107,18599-604, https://doi.org/10.1073/pnas.1009778107 [3] Ferrari, V et al. New Insights into the Mechanisms of Proteasome-Mediated Peptide Splicing Learned from Comparing Splicing Efficiency by Different Proteasome Subtypes. J Immunol., 2022, 208, 2817-2828. https://doi.org/10.4049/jimmunol.2101198.
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Vigneron, N., Ferrari, V., Stroobant, V., & Van den Eynde, B. (2023). Understanding the mechanisms of Proteasome-Mediated Peptide Splicing by Comparing Splicing Efficiency by Different Proteasome Subtypes. 5th International Caparica Conference in SPLICING 2023, Caparica, Portugal. https://hdl.handle.net/2078.5/241599