ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum

Abstract

The ability of killer T cells carrying the CD8 antigen to detect tumours or intracellular pathogens requires an extensive display of antigenic peptides by major histocompatibility complex (MHC) class I molecules on the surface of potential target cells. These peptides are derived from almost all intracellular proteins and reveal the presence of foreign pathogens and mutations. How cells produce thousands of distinct peptides cleaved to the precise lengths required for binding different MHC class I molecules remains unknown. The peptides are cleaved from endogenously synthesized proteins by the proteasome in the cytoplasm and then trimmed by an unknown aminopeptidase in the endoplasmic reticulum (ER). Here we identify ERAAP, the aminopeptidase associated with antigen processing in the ER. ERAAP has a broad substrate specificity, and its expression is strongly upregulated by interferon-gamma. Reducing the expression of ERAAP through RNA interference prevents the trimming of peptides for MHC class I molecules in the ER and greatly reduces the expression of MHC class I molecules on the cell surface. Thus, ERAAP is the missing link between the products of cytosolic processing and the final peptides presented by MHC class I molecules on the cell surface.

Critical Role of Endoplasmic Reticulum Aminopeptidase 1 in Determining the Length and Sequence of Peptides Bound and Presented by HLA–B27

“…As an aminopeptidase located in the endoplasmic reticulum (ER), ERAP1 trims peptides to optimal length (usually 8-10 mer) before proceeding to bind to class I major histocompatibility complex (MHC) molecules (8)(9)(10). Strikingly, ERAP1 polymorphisms only affect the risk of AS in HLA-B27-positive individuals (7).…”

Quantitative modeling of peptide binding to TAP using support vector machine

“…SVM-Models trained using sparse sequence representation were selected. (A) Predictive performance (R p ) of SVM-models with regard to the fragment size used for training (1)(2)(3)(4)(5)(6)(7)(8)(9). Only the largest R p value achieved by a specific model (indicated in the abscissa) at each fragment size is represented.…”

Microenvironmental stresses induce HLA‐E/Qa‐1 surface expression and thereby reduce CD8+ T‐cell recognition of stressed cells

“…This peptide is derived from endogenous Fam49b and the antigen-experienced CD8 + T cells were frequently observed in naïve mice. Since ERAAP is an indispensable aminopeptidase in charge of trimming the long precursors of antigenic peptides transported in the ER [48], CD8 + T cells are hence able to exploit Qa-1 molecules for monitoring a defect in antigen processing [16]. Defects in MHC I antigen processing machinery are frequently observed among a variety of tumors, and we therefore asked an another possibility in which αβ TCR of CD8 + T cells is capable to recognize the stress-induced pQa-1 in order to sense "stresses" by means of unusual peptide presentation.…”

“…This peptide is derived from endogenous Fam49b and the antigen-experienced CD8 + T cells were frequently observed in naïve mice. Since ERAAP is an indispensable aminopeptidase in charge of trimming the long precursors of antigenic peptides transported in the ER [48], CD8 + …”