The Role of Aminopeptidase ERAP1 in Human Pathology-A Review

Abstract

Aminopeptidases are a group of enzymatic proteins crucial for protein digestion, catalyzing the cleavage of amino acids at the N-terminus of peptides. Among them are ERAP1 (coding for endoplasmic reticulum aminopeptidase 1), ERAP2 (coding for endoplasmic reticulum aminopeptidase 2), and LNPEP (coding for leucyl and cystinyl aminopeptidase). These genes encoding these enzymes are contiguous and located on the same chromosome (5q21); they share structural homology and functions and are associated with immune-mediated diseases. These aminopeptidases play a key role in immune pathology by cleaving peptides to optimal sizes for binding to the major histocompatibility complex (MHC) and contribute to cellular homeostasis. By their ability to remove the extracellular region of interleukin 2 and 6 receptors (IL2, IL6) and the tumor necrosis factor receptor (TNF), ERAP1 and ERAP2 are involved in regulating the innate immune response and, finally, in blood pressure control and angiogenesis. The combination of specific genetic variations in these genes has been linked to various conditions, including autoimmune and autoinflammatory diseases and cancer, as well as hematological and dermatological disorders. This literature review aims to primarily explore the impact of ERAP1 polymorphisms on its enzymatic activity and function. Through a systematic examination of the available literature, this review seeks to provide valuable insights into the role of ERAP1 in the pathogenesis of various diseases and its potential implications for targeted therapeutic interventions. Through an exploration of the complex interplay between ERAP1 and various disease states, this review contributes to the synthesis of current biomedical research findings and their implications for personalized medicine.

Keywords: ERAP1; ERAP2; LNEP; aminopeptidases; major histocompatibility complex.

Figure 1

Domain structure of ERAP1 gene and protein with autoimmune-associated SNPs: the ERAP1 gene spans 48kb in length. The ERAP1 protein consists of four domains: Domain I shown in light blue, Domain II in green, Domain III in pink, and Domain IV in orange. The active site of Domain II, containing GAMEN and HEXXHX motifs, is highlighted in dark blue. Single-nucleotide polymorphisms (SNPs) associated with autoimmune pathology are indicated with thin blue underlines. This figure was adapted from figure in [7].

Figure 2

The polymorphic role of ERAP1—ERAP1 plays a polymorphic role in antigen processing for presentation on MHC I molecules at the cell membrane surface. Beyond its involvement in antigen presentation, ERAP1 also aids in the expression of cytokine receptors such as IL-6R, TNFR, and IL-1RII on the cell membrane surface, and it boosts macrophage activation and phagocytosis. This figure was adapted from figure in [7].

Figure 3

Tissue specificity in MHC-I-opathy. Antigenic structures at the level of different external or internal sites involved in MHC-I-opathies. * is used in Human Leukocyte Antigen (HLA) nomenclature to denote genetic polymorphisms or allelic variants within the respective HLA gene loci. https://hla.alleles.org/nomenclature/index.html.

Figure 4

Relationship between HLA-B27 and ERAP1 in AS.

Figure 5

Interrelationship between ERAP1, HLA class I, and autoimmune diseases. * is used in Human Leukocyte Antigen (HLA) nomenclature to denote genetic polymorphisms or allelic variants within the respective HLA gene loci.