The HLA Ligandome Comprises a Limited Repertoire of O-GlcNAcylated Antigens Preferentially Associated With HLA-B*07:02

Soumya Mukherjee, Alvaro Sanchez-Bernabeu, Laura C. Demmers, Wei Wu, Albert J.R. Heck*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Mass-spectrometry based immunopeptidomics has provided unprecedented insights into antigen presentation, not only charting an enormous ligandome of self-antigens, but also cancer neoantigens and peptide antigens harbouring post-translational modifications. Here we concentrate on the latter, focusing on the small subset of HLA Class I peptides (less than 1%) that has been observed to be post-translationally modified (PTM) by a O-linked N-acetylglucosamine (GlcNAc). Just like neoantigens these modified antigens may have specific immunomodulatory functions. Here we compiled from literature, and a new dataset originating from the JY B cell lymphoblastoid cell line, a concise albeit comprehensive list of O-GlcNAcylated HLA class I peptides. This cumulative list of O-GlcNAcylated HLA peptides were derived from normal and cancerous origin, as well as tissue specimen. Remarkably, the overlap in detected O-GlcNAcylated HLA peptides as well as their source proteins is strikingly high. Most of the O-GlcNAcylated HLA peptides originate from nuclear proteins, notably transcription factors. From this list, we extract that O-GlcNAcylated HLA Class I peptides are preferentially presented by the HLA-B*07:02 allele. This allele loads peptides with a Proline residue anchor at position 2, and features a binding groove that can accommodate well the recently proposed consensus sequence for O-GlcNAcylation, P(V/A/T/S)g(S/T), essentially explaining why HLA-B*07:02 is a favoured binding allele. The observations drawn from the compiled list, may assist in the prediction of novel O-GlcNAcylated HLA antigens, which will be best presented by patients harbouring HLA-B*07:02 or related alleles that use Proline as anchoring residue.

Original languageEnglish
Article number796584
Pages (from-to)1-10
JournalFrontiers in Immunology
Volume12
DOIs
Publication statusPublished - 1 Dec 2021

Bibliographical note

Funding Information:
We would like to acknowledge support for this research through the NWO funded Netherlands Proteomics Centre through the National Road Map for Large-scale Infrastructures program X-Omics (Project 184.034.019). LD and AH are further supported by the NWO Gravitation program Institute for Chemical Immunology (ICI00003). We acknowledge Dr. Stefan Stevanović (University of Tubingen, Germany) for providing the pan-HLA antibody W6/32.

Funding Information:
We would like to acknowledge support for this research through the NWO funded Netherlands Proteomics Centre through the National Road Map for Large-scale Infrastructures program X-Omics (Project 184.034.019). LD and AH are further supported by the NWO Gravitation program Institute for Chemical Immunology (ICI00003). We acknowledge Dr. Stefan Stevanovi? (University of Tubingen, Germany) for providing the pan-HLA antibody W6/32.

Publisher Copyright:
Copyright © 2021 Mukherjee, Sanchez-Bernabeu, Demmers, Wu and Heck.

Funding

We would like to acknowledge support for this research through the NWO funded Netherlands Proteomics Centre through the National Road Map for Large-scale Infrastructures program X-Omics (Project 184.034.019). LD and AH are further supported by the NWO Gravitation program Institute for Chemical Immunology (ICI00003). We acknowledge Dr. Stefan Stevanovi? (University of Tubingen, Germany) for providing the pan-HLA antibody W6/32.

Keywords

  • HLA
  • HLA-B*07:02
  • immunopeptidome
  • MHC
  • neo-antigen
  • O-GlcNAcylation modification

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