Quantitative measurement of the requirement of diverse protein degradation pathways in MHC class I peptide presentation

Peptides from degradation of intracellular proteins are continuously displayed by major histocompatibility complex (MHC) class I. To better understand origins of these peptides, we performed a comprehensive census of the class I peptide repertoire in the presence and absence of ubiquitin-proteasome...

Full description

Saved in:
Bibliographic Details
Published in:Science advances 2023-06, Vol.9 (25), p.eade7890-eade7890
Main Authors: Mamrosh, Jennifer L, Sherman, David J, Cohen, Joseph R, Johnston, James A, Joubert, Marisa K, Li, Jing, Lipford, J Russell, Lomenick, Brett, Moradian, Annie, Prabhu, Siddharth, Sweredoski, Michael J, Vander Lugt, Bryan, Verma, Rati, Deshaies, Raymond J
Format: Article
Language:English
Subjects:
Antigen Presentation
Biomedicine and Life Sciences
Histocompatibility Antigens Class I - metabolism
Immunology
Peptides - metabolism
Proteasome Endopeptidase Complex - metabolism
Proteolysis
SciAdv r-articles
Ubiquitin - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Peptides from degradation of intracellular proteins are continuously displayed by major histocompatibility complex (MHC) class I. To better understand origins of these peptides, we performed a comprehensive census of the class I peptide repertoire in the presence and absence of ubiquitin-proteasome system (UPS) activity upon developing optimized methodology to enrich for and quantify these peptides. Whereas most class I peptides are dependent on the UPS for their generation, a surprising 30%, enriched in peptides of mitochondrial origin, appears independent of the UPS. A further ~10% of 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 atypical peptides. 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, alternative protein degradation pathways also generate class I peptides when canonical pathways are impaired.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.ade7890