Endoplasmic Reticulum Aminopeptidase 2 (ERAP2) is an enzyme located within the endoplasmic reticulum (ER) of immune and other cells. As a member of the M1 family of aminopeptidases, its function is linked to the body’s ability to distinguish between its own components and foreign invaders. ERAP2 acts as a molecular trimmer, processing protein fragments before they are displayed on the cell surface for immune system inspection. This enzyme plays a role in immune surveillance and its activity is induced by inflammatory signals like interferon-gamma.
Molecular Function in Antigen Presentation
The primary role of ERAP2 is to refine the precursors of antigenic peptides, which are short chains of amino acids derived from broken-down proteins inside the cell. These precursor peptides are transported into the ER, where they must be trimmed to a precise length. This trimming allows them to fit correctly into the groove of Major Histocompatibility Complex Class I (MHC-I) molecules. MHC-I molecules are surface proteins that present these peptides to CD8+ T-cells, the immune system’s cytotoxic “killer” cells.
ERAP2 works alongside the related enzyme ERAP1 in antigen processing. While ERAP1 favors trimming peptides with hydrophobic amino acids, ERAP2 prefers peptides starting with positively charged residues, particularly arginine. This distinct substrate specificity means ERAP2 shapes a different set of peptides than ERAP1, increasing the diversity of antigens presented to the immune system. By ensuring the peptides are the optimal length, ERAP2 stabilizes the MHC-I molecule, which is necessary for a robust T-cell response against infected or abnormal cells.
Genetic Variations and Protein Expression
The ERAP2 gene is highly polymorphic, existing in several common alleles within the human population. This genetic variability has evolved under balancing selection, maintaining two differentiated groups of variations: Haplotype A and Haplotype B. The most significant functional variation is a single nucleotide polymorphism (SNP), tagged by rs2248374, which determines whether the full-length, active ERAP2 protein is expressed.
The G allele of this SNP introduces a change that leads to a premature stop signal in the messenger RNA (mRNA) transcript. This non-functional mRNA is destroyed through nonsense-mediated decay (NMD). Consequently, individuals homozygous for the G allele (Haplotype B) do not produce the active ERAP2 enzyme. This variation creates two functional groups in the population: those who express the active enzyme and those who are essentially ERAP2-null.
Influence on Autoimmune Conditions
The presence or absence of the functional ERAP2 protein, dictated by genetic variants, influences an individual’s risk for various autoimmune diseases. The underlying mechanism connects the enzyme’s trimming function to T-cell activation against healthy tissues. When ERAP2’s activity is altered or absent, the repertoire of self-peptides presented by MHC-I molecules changes, potentially revealing antigens that T-cells misinterpret as foreign.
ERAP2 variants are associated with conditions like ankylosing spondylitis (AS), psoriasis, and Behçet’s disease. In AS and birdshot chorioretinopathy, the absence of the full-length ERAP2 protein is often protective against disease development. Conversely, in psoriasis, the gene’s association depends on the presence of specific MHC-I alleles, such as HLA-C06:02. The genetic interplay between ERAP2 and MHC-I suggests that the risk for autoimmunity stems from a failure in the peptide-editing machinery.
Role in Infectious Disease Response
ERAP2’s influence on immune health extends to how the body responds to pathogens, including bacteria and viruses. The enzyme’s role in optimizing antigen presentation is important for CD8+ T-cells to quickly recognize and eliminate infected cells. Genetic variants that lead to higher ERAP2 activity can be protective against certain infections by ensuring foreign antigens are efficiently processed and displayed.
Studies show that genetic variants associated with decreased ERAP2 expression were detrimental during historical epidemics, such as the Black Death (Yersinia pestis). Furthermore, decreased ERAP2 expression is linked to an increased risk of severe respiratory infections, including pneumonia. This suggests a balancing selection pressure: the variant that protects against some autoimmune conditions may leave individuals more susceptible to severe outcomes during infectious outbreaks. ERAP2’s involvement in the Renin-Angiotensin System (RAS) also suggests a secondary role in viral infections like COVID-19, where defective ERAP2 variants may exacerbate disease severity through effects on blood pressure and inflammation.