MassIVE MSV000091285

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Quantitative Measurement of the Requirement of Diverse Protein Degradation Pathways in MHC Class I Peptide Presentation

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Description

The adaptive immune system distinguishes self from non-self by surveying peptides generated from degradation of intracellular proteins that are loaded onto MHC Class I molecules for display on the cell surface. While early studies reported that the bulk of cell surface MHC Class I complexes require the ubiquitin-proteasome system (UPS) for their generation, this conclusion has been challenged. To better understand MHC Class I peptide origins, we sought to carry out a comprehensive, quantitative census of the MHC Class I peptide repertoire in the presence and absence of UPS activity. We introduce optimized methodology to enrich for authentic Class I-bound peptides in silico and then quantify by mass spectrometry their relative amounts upon perturbation of the ubiquitin-proteasome system. Whereas most peptides are dependent on the proteasome and ubiquitination for their generation, a surprising 30% of the MHC Class I repertoire, enriched in peptides of mitochondrial origin, appears independent of these pathways. A further ~10% of Class I-bound peptides were found to be dependent on the proteasome but independent of ubiquitination for their generation. Notably, clinically achievable partial inhibition of the proteasome resulted in display of novel peptide antigens. Our results suggest that generation of MHC Class I/peptide complexes is more complex than previously recognized, with UPS-dependent and UPS-independent components; paradoxically, a smaller number of atypical peptides increase in presentation when canonical pathways are impaired. -------------------------------------------------------------------------------------------------------------Please see supplementary file S1.xlsx for a detailed file description. [doi:10.25345/C5RJ49478] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: antigen ; MHC Class I ; immunopeptidome ; immunopeptidomics ; proteasome ; ubiquitin

Contact

Principal Investigators:
(in alphabetical order) 		Ray Deshaies, Amgen, USA
Submitting User: mamro001

Publications

Mamrosh JL, Sherman DJ, Cohen JR, Johnston JA, Joubert MK, Li J, Lipford JR, Lomenick B, Moradian A, Prabhu S, Sweredoski MJ, Vander Lugt B, Verma R, Deshaies RJ.
Quantitative measurement of the requirement of diverse protein degradation pathways in MHC class I peptide presentation.
Sci Adv. 2023 Jun 23;9(25):eade7890. Epub 2023 Jun 23.

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