New Insights into the Mechanisms of Proteasome-Mediated Peptide Splicing Learned from Comparing Splicing Efficiency by Different Proteasome Subtypes
(2022) Journal of Immunology — Vol. 208, n° 12, p. 2817-2828 (2022)
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- Authors
Naulaerts, Stefan 
Vigneron, Nathalie
- Abstract
- By tying peptide fragments originally distant in parental proteins, the proteasome can generate spliced peptides that are recognized by cytolytic T lymphocytes. This occurs by transpeptidation involving a peptide-acyl-enzyme intermediate and another peptide fragment present in the catalytic chamber. Four main subtypes of proteasomes exist: the standard proteasome (SP), the immunoproteasome (IP) and intermediate proteasomes β1-β2-β5i (SIP) and β1i-β2-β5i (DIP). Here, we use a TMT-quantification approach to study the production of six spliced human antigenic peptides by the four proteasome subtypes. Peptides FGF-5(172-176/217-220), tyrosinase(368-373/336-340) and gp100(40-42/47-52), are better produced by the SP than the other proteasome subtypes. The peptides SP110(296-301/286-289), gp100(195-202/191or192) and gp100(47-52/40-42) 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 peptides RTK_QLYPEW and QLYPEW_RTK are composed of identical splicing partners, their production varies differently according to the proteasome subtype. These differences were maintained after in vitro digestions involving identical amounts of the splicing fragments. Our results indicate that the amount of splicing partner is not the only factor driving peptide splicing, and suggest that peptide splicing efficiency also relies on other factors such as the affinity of the C-terminal splice reactant for the primed binding site of the catalytic subunit.
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Citations
Ferrari, V., Stroobant, V., Abi Habib, J., Naulaerts, S., Van den Eynde, B., & Vigneron, N. (2022). New Insights into the Mechanisms of Proteasome-Mediated Peptide Splicing Learned from Comparing Splicing Efficiency by Different Proteasome Subtypes. Journal of Immunology, 208(12), 2817-2828. https://doi.org/10.4049/jimmunol.2101198 (Original work published 2022)