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.

A New ERAP2/Iso3 Isoform Expression Is Triggered by Different Microbial Stimuli in Human Cells. Could It Play a Role in the Modulation of SARS-CoV-2 Infection?

“…The involvement of ERAPs in modulating viral infections is widely recognized as recently reviewed in [ 34 ]. Several studies, indeed, have demonstrated the intervention of ERAP genetic variants in the life cycle of HCV, flu, CMV, HPV, HIV, and other pathogens at different levels.…”

Impact of Natural Occurring ERAP1 Single Nucleotide Polymorphisms within miRNA-Binding Sites on HCMV Infection

“…The role of ERAP1 in modulating susceptibility to infections from HCV, HCMV, influenza virus, HPV, HIV, and toxoplasma has been exhaustively reviewed by Saulle et al [59] and Yao et al [60]. Several ERAP1 variants affecting disease susceptibility and/or progression have been identified.…”

“…They were located both in coding (rs30187, rs27044, rs26618, rs10050860, rs26618, rs26653, rs17481856) and non-coding regions, including intronic (rs149481, rs27042, rs149173, rs17481856) and 3 UTR (rs17481334) regions. Genetic variants in the ERAP1 coding region-rs27044, rs26653, rs10050860, rs26618, rs26653, rs17481856, and rs30187-have been associated with susceptibility to HIV, HCV, HPV, and/or toxoplasmosis infection [59,60]. The intronic variants rs149481, rs27042, rs149173, and rs17481856 have been associated with susceptibility to Toxoplasma gondii infection, Kawasaki disease, chronic hepatitis C, and HIV [59,60].…”

“…Genetic variants in the ERAP1 coding region-rs27044, rs26653, rs10050860, rs26618, rs26653, rs17481856, and rs30187-have been associated with susceptibility to HIV, HCV, HPV, and/or toxoplasmosis infection [59,60]. The intronic variants rs149481, rs27042, rs149173, and rs17481856 have been associated with susceptibility to Toxoplasma gondii infection, Kawasaki disease, chronic hepatitis C, and HIV [59,60]. Interestingly, most of these SNPs have also been associated with essential hypertension and autoimmune diseases, including AS, MS, psoriasis, and BD [56,59,60].…”

“…The intronic variants rs149481, rs27042, rs149173, and rs17481856 have been associated with susceptibility to Toxoplasma gondii infection, Kawasaki disease, chronic hepatitis C, and HIV [59,60]. Interestingly, most of these SNPs have also been associated with essential hypertension and autoimmune diseases, including AS, MS, psoriasis, and BD [56,59,60].…”