Estimating the Contribution of Proteasomal Spliced Peptides to the HLA-I Ligandome*

peer-reviewed · Molecular & Cellular Proteomics · 2018

peer-reviewed · Molecular & Cellular Proteomics · 2018. Roman Mylonas et al. Spliced peptides are short protein fragments spliced together in the proteasome by peptide bond formation…
Date 2018-12-01
Type peer-reviewed
Venue Molecular & Cellular Proteomics
Publisher Elsevier BV
Contribution downstream-application
DOI 10.1074/mcp.ra118.000877
Citations (OpenAlex) 100
Venue 2-year citedness 4.69

Preprint version: Estimating the Contribution of Proteasomal Spliced Peptides to the HLA-I Ligandome (2018-03-26, bioRxiv)

Abstract

Spliced peptides are short protein fragments spliced together in the proteasome by peptide bond formation. True estimation of the contribution of proteasome-spliced peptides (PSPs) to the global human leukocyte antigen (HLA) ligandome is critical. A recent study suggested that PSPs contribute up to 30% of the HLA ligandome. We performed a thorough reanalysis of the reported results using multiple computational tools and various validation steps and concluded that only a fraction of the proposed PSPs passes the quality filters. To better estimate the actual number of PSPs, we present an alternative workflow. We performed de novo sequencing of the HLA-peptide spectra and discarded all de novo sequences found in the UniProt database. We checked whether the remaining de novo sequences could match spliced peptides from human proteins. The spliced sequences were appended to the UniProt fasta file, which was searched by two search tools at a false discovery rate (FDR) of 1%. We find that 2-6% of the HLA ligandome could be explained as spliced protein fragments. The majority of these potential PSPs have good peptide-spectrum match properties and are predicted to bind the respective HLA molecules. However, it remains to be shown how many of these potential PSPs actually originate from proteasomal splicing events.

Authors

  1. Roman Mylonas · SIB Swiss Institute of Bioinformatics
  2. Ilan Beer
  3. Christian Iseli · SIB Swiss Institute of Bioinformatics
  4. Chloe Chong · Centre Hospitalier Universitaire Vaudois, Ludwig Cancer Research, University of Lausanne
  5. Hui-Song Pak · Centre Hospitalier Universitaire Vaudois, Ludwig Cancer Research, University of Lausanne
  6. David Gfeller · Ludwig Cancer Research, SIB Swiss Institute of Bioinformatics, University of Lausanne
  7. George Coukos · Centre Hospitalier Universitaire Vaudois, Ludwig Cancer Research, University of Lausanne
  8. Ioannis Xenarios · SIB Swiss Institute of Bioinformatics
  9. Markus Müller · SIB Swiss Institute of Bioinformatics
  10. Michal Bassani-Sternberg · Centre Hospitalier Universitaire Vaudois, Ludwig Cancer Research, SIB Swiss Institute of Bioinformatics, University of Lausanne

Methods and tools

  • Proteasomal spliced peptide estimation: Uses de novo sequencing of HLA-I peptide spectra, filtered against UniProt and matched to spliced candidates, to estimate how many ligands are proteasome-spliced.

Methods it uses

  • PEAKS: Commercial DP-based de novo

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