TY - JOUR
T1 - The ER Aminopeptidases, ERAP1 and ERAP2, synergize to self-modulate their respective activities
AU - Martín-Esteban, Adrian
AU - Rodriguez, Jesus Contreras
AU - Peske, David
AU - Lopez de Castro, Jose A.
AU - Shastri, Nilabh
AU - Sadegh-Nasseri, Scheherazade
N1 - Publisher Copyright:
Copyright © 2022 Martín-Esteban, Rodriguez, Peske, Lopez de Castro, Shastri and Sadegh-Nasseri.
PY - 2022/12/8
Y1 - 2022/12/8
N2 - Introduction: Critical steps in Major Histocompatibility Complex Class I (MHC-I) antigen presentation occur in the endoplasmic reticulum (ER). In general, peptides that enter the ER are longer than the optimal length for MHC-I binding. The final trimming of MHC-I epitopes is performed by two related aminopeptidases, ERAP1 and ERAP2 in humans that possess unique and complementary substrate trimming specificities. While ERAP1 efficiently trims peptides longer than 9 residues, ERAP2 preferentially trims peptides shorter than 9 residues. Materials and Methods: Using a combination of biochemical and proteomic studies followed by biological verification. Results: We demonstrate that the optimal ligands for either enzyme act as inhibitors of the other enzyme. Specifically, the presence of octamers reduced the trimming of long peptides by ERAP1, while peptides longer than nonomers inhibit ERAP2 activity. Discussion: We propose a mechanism for how ERAP1 and ERAP2 synergize to modulate their respective activities and shape the MHC-I peptidome by generating optimal peptides for presentation.
AB - Introduction: Critical steps in Major Histocompatibility Complex Class I (MHC-I) antigen presentation occur in the endoplasmic reticulum (ER). In general, peptides that enter the ER are longer than the optimal length for MHC-I binding. The final trimming of MHC-I epitopes is performed by two related aminopeptidases, ERAP1 and ERAP2 in humans that possess unique and complementary substrate trimming specificities. While ERAP1 efficiently trims peptides longer than 9 residues, ERAP2 preferentially trims peptides shorter than 9 residues. Materials and Methods: Using a combination of biochemical and proteomic studies followed by biological verification. Results: We demonstrate that the optimal ligands for either enzyme act as inhibitors of the other enzyme. Specifically, the presence of octamers reduced the trimming of long peptides by ERAP1, while peptides longer than nonomers inhibit ERAP2 activity. Discussion: We propose a mechanism for how ERAP1 and ERAP2 synergize to modulate their respective activities and shape the MHC-I peptidome by generating optimal peptides for presentation.
KW - HLA
KW - aminopeptidase
KW - antigen processing
KW - epitope generation
KW - mechanism
KW - peptidome
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U2 - 10.3389/fimmu.2022.1066483
DO - 10.3389/fimmu.2022.1066483
M3 - Article
C2 - 36569828
AN - SCOPUS:85144637358
SN - 1664-3224
VL - 13
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 1066483
ER -