TY - JOUR
T1 - The biogenesis of the immunopeptidome
AU - Admon, Arie
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/5
Y1 - 2023/5
N2 - The immunopeptidome is the repertoire of peptides bound and presented by the MHC class I, class II, and non-classical molecules. The peptides are produced by the degradation of most cellular proteins, and in some cases, peptides are produced from extracellular proteins taken up by the cells. This review attempts to first describe some of its known and well-accepted concepts, and next, raise some questions about a few of the established dogmas in this field: The production of novel peptides by splicing is questioned, suggesting here that spliced peptides are extremely rare, if existent at all. The degree of the contribution to the immunopeptidome by degradation of cellular protein by the proteasome is doubted, therefore this review attempts to explain why it is likely that this contribution to the immunopeptidome is possibly overstated. The contribution of defective ribosome products (DRiPs) and non-canonical peptides to the immunopeptidome is noted and methods are suggested to quantify them. In addition, the common misconception that the MHC class II peptidome is mostly derived from extracellular proteins is noted, and corrected. It is stressed that the confirmation of sequence assignments of non-canonical and spliced peptides should rely on targeted mass spectrometry using spiking-in of heavy isotope-labeled peptides. Finally, the new methodologies and modern instrumentation currently available for high throughput kinetics and quantitative immunopeptidomics are described. These advanced methods open up new possibilities for utilizing the big data generated and taking a fresh look at the established dogmas and reevaluating them critically.
AB - The immunopeptidome is the repertoire of peptides bound and presented by the MHC class I, class II, and non-classical molecules. The peptides are produced by the degradation of most cellular proteins, and in some cases, peptides are produced from extracellular proteins taken up by the cells. This review attempts to first describe some of its known and well-accepted concepts, and next, raise some questions about a few of the established dogmas in this field: The production of novel peptides by splicing is questioned, suggesting here that spliced peptides are extremely rare, if existent at all. The degree of the contribution to the immunopeptidome by degradation of cellular protein by the proteasome is doubted, therefore this review attempts to explain why it is likely that this contribution to the immunopeptidome is possibly overstated. The contribution of defective ribosome products (DRiPs) and non-canonical peptides to the immunopeptidome is noted and methods are suggested to quantify them. In addition, the common misconception that the MHC class II peptidome is mostly derived from extracellular proteins is noted, and corrected. It is stressed that the confirmation of sequence assignments of non-canonical and spliced peptides should rely on targeted mass spectrometry using spiking-in of heavy isotope-labeled peptides. Finally, the new methodologies and modern instrumentation currently available for high throughput kinetics and quantitative immunopeptidomics are described. These advanced methods open up new possibilities for utilizing the big data generated and taking a fresh look at the established dogmas and reevaluating them critically.
KW - Antigen processing and presentation APP
KW - HLA
KW - Immunopeptidome
KW - MHC, peptidome
KW - Proteasome
KW - Spliced peptides
UR - http://www.scopus.com/inward/record.url?scp=85153961377&partnerID=8YFLogxK
U2 - 10.1016/j.smim.2023.101766
DO - 10.1016/j.smim.2023.101766
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AN - SCOPUS:85153961377
SN - 1044-5323
VL - 67
JO - Seminars in Immunology
JF - Seminars in Immunology
M1 - 101766
ER -