An Overview on ERAP Roles in Infectious Diseases

Abstract

Endoplasmic reticulum (ER) aminopeptidases ERAP1 and ERAP2 (ERAPs) are crucial enzymes shaping the major histocompatibility complex I (MHC I) immunopeptidome. In the ER, these enzymes cooperate in trimming the N-terminal residues from precursors peptides, so as to generate optimal-length antigens to fit into the MHC class I groove. Alteration or loss of ERAPs function significantly modify the repertoire of antigens presented by MHC I molecules, severely affecting the activation of both NK and CD8⁺ T cells. It is, therefore, conceivable that variations affecting the presentation of pathogen-derived antigens might result in an inadequate immune response and onset of disease. After the first evidence showing that ERAP1-deficient mice are not able to control Toxoplasma gondii infection, a number of studies have demonstrated that ERAPs are control factors for several infectious organisms. In this review we describe how susceptibility, development, and progression of some infectious diseases may be affected by different ERAPs variants, whose mechanism of action could be exploited for the setting of specific therapeutic approaches.

Keywords: ERAPs; HIV; infection diseases; polymorphisms.

Figure 1

Genomic structure of the human ERAP1 (A) and ERAP2 (B) genes. Exons are numbered and depicted as boxes. Outlines indicate the sites of exonic or intronic polymorphisms described in the text as rs and related infections.

Figure 2

Schematic representation of the mechanism of action displayed by ERAP2 ISO3 and ISO4 in the antigen presentation pathway. (A). Following virus infection rs2248374-A ERAP2 expressing cells produce wild type ERAP2 (ERAP2-wt) which can homodimerize or heterodimerize with ERAP1-wt (ERAP2-wt⁺ERAP2-wt; ERAP1-wt⁺ERAP2-wt), in order to process viral antigens to be presented on cell surface for recognition by specific cytotoxic T lymphocyte (CTL) clones. (B). Following virus infection rs2248374-G ERAP2 expressing cells may transcribe two alternative spliced isoforms: ERAP2-ISO3 and ERAP2-ISO4. This two variants, unlike ERAP2-wt, lack the catalytic domain but can still heterodimerize with both ERAP2-wt and ERAP1-wt. As a result, these unconventional heterodimers (ISO3⁺ERAP2-wt; ISO3⁺ERAP1-wt; ISO4⁺ERAP2-wt; ISO4⁺ERAP1-wt) may process viral antigens differently from the canonical ones, generating an alternative antigenic repertoire. This in turn may activate other CTL clones and more broadly a more or less protective response by the immune system.