ERAP1 Gene: Function, Disease Associations, and Clinical Significance
Comprehensive resource on ERAP1 (Endoplasmic Reticulum Aminopeptidase 1), including its role in antigen processing, genetic variants, and links to autoimmune diseases and cancer.
Gene Information Card
| Symbol | ERAP1 |
|---|---|
| Full Name | Endoplasmic Reticulum Aminopeptidase 1 |
| Gene Type | protein-coding |
| Chromosomal Location | 5q15.3 |
| NCBI Gene ID | 51752 ncbi.nlm.nih.gov/gene/51752 |
| Ensembl ID | ENSG00000164307 |
| UniProt ID | Q9NZ08 |
| OMIM ID | 606832 |
| HGNC ID | 18173 |
| Aliases | ARTS-1, ALAP, ERAAP, KIAA0525, PILS-AP |
Description
ERAP1 (Endoplasmic Reticulum Aminopeptidase 1) encodes a zinc metallopeptidase of the M1 family. It is primarily localized in the endoplasmic reticulum (ER) and plays a critical role in the final trimming of antigenic peptide precursors to the optimal length (typically 8-10 amino acids) for loading onto MHC class I molecules. This process is essential for the adaptive immune response against intracellular pathogens and tumors. Beyond its role in antigen processing, ERAP1 is also involved in the shedding of cytokine receptors (e.g., TNF-R1, IL-6Rα) and the regulation of blood pressure through the processing of angiotensin II. Genetic variants in ERAP1 have been strongly associated with several autoimmune diseases, particularly ankylosing spondylitis, and are being investigated for their role in cancer and other conditions.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Ankylosing Spondylitis | Specific ERAP1 SNPs (e.g., rs30187, rs27044) alter the enzyme's activity and substrate specificity, leading to changes in the repertoire of peptides presented by HLA-B27. This altered peptide presentation is thought to trigger an aberrant immune response and disease pathogenesis. | Genome-wide association studies (GWAS) have consistently identified ERAP1 as a major susceptibility locus for ankylosing spondylitis, particularly in HLA-B27-positive individuals. Functional studies confirm the impact of these variants on peptide trimming. |
| Birdshot Chorioretinopathy | Similar to ankylosing spondylitis, ERAP1 variants are associated with this rare autoimmune eye disease, which is strongly linked to HLA-A29. The mechanism is believed to involve altered antigen processing and presentation, affecting the T-cell response. | GWAS studies have found significant associations between ERAP1 SNPs and birdshot chorioretinopathy, implicating the same pathway of altered peptide presentation. |
| Psoriasis | ERAP1 variants have been associated with psoriasis susceptibility. The mechanism is thought to involve altered peptide presentation by HLA-C*06:02, leading to an abnormal skin-specific T-cell response. | Multiple GWAS and meta-analyses have identified ERAP1 as a risk locus for psoriasis, with the effect being most pronounced in individuals carrying the HLA-C risk allele. |
| Cancer | ERAP1 expression is often dysregulated in various cancers. Its role is complex; it can be tumor-suppressive by generating immunogenic peptides for T-cell recognition, or tumor-promoting by generating suppressive peptides or altering the expression of cell surface molecules, leading to immune evasion. | Expression studies show altered ERAP1 levels in tumors (e.g., cervical, lung, colorectal). Functional studies demonstrate that modulating ERAP1 expression affects tumor cell recognition by cytotoxic T lymphocytes (CTLs). |
| Hypertension | ERAP1 can cleave angiotensin II, a key regulator of blood pressure. Variants that alter its enzymatic activity may influence angiotensin II levels and contribute to blood pressure regulation. | Association studies have linked ERAP1 variants to blood pressure and hypertension, though the effect is modest. Functional studies confirm its role in angiotensin II metabolism. |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Lymph node | 22.4 | High |
| Spleen | 20.1 | High |
| Appendix | 18.7 | High |
| Tonsil | 17.9 | High |
| Bone marrow | 15.2 | High |
| Lung | 12.8 | Medium |
| Small intestine | 11.5 | Medium |
| Kidney | 10.9 | Medium |
| Liver | 8.3 | Medium |
| Brain | 4.1 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| BJ (fibroblast) | 18.5 | High expression |
| K-562 (leukemia) | 16.2 | High expression |
| A549 (lung carcinoma) | 14.8 | Medium expression |
| HeLa (cervical carcinoma) | 13.1 | Medium expression |
| MCF7 (breast carcinoma) | 11.9 | Medium expression |
| HepG2 (hepatocellular carcinoma) | 9.7 | Medium expression |
| SH-SY5Y (neuroblastoma) | 6.3 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| rs30187 (K528R) | Missense | ~40% (European) | Alters enzyme activity and substrate specificity. Strongly associated with ankylosing spondylitis. |
| rs27044 (Q730E) | Missense | ~35% (European) | Affects peptide trimming efficiency. Associated with ankylosing spondylitis and birdshot chorioretinopathy. |
| rs17482078 (R127P) | Missense | ~5% (European) | Reduces ERAP1 enzymatic activity. Protective against ankylosing spondylitis. |
| rs26653 (M349V) | Missense | ~30% (European) | Influences ERAP1 expression and activity. Associated with various autoimmune conditions. |
| rs2287987 (M349V) | Missense | ~30% (European) | Impacts ERAP1 function and is linked to altered peptide repertoire. |
Mutation functional classification
Loss of Function (LOF)
Variants like rs17482078 (R127P) are considered loss-of-function, as they significantly reduce the enzyme's catalytic activity. This reduction is protective against diseases like ankylosing spondylitis, suggesting that excessive ERAP1 activity contributes to pathogenesis.
Gain of Function (GOF)
Some variants, such as rs30187 (K528R), are considered gain-of-function or altered-function. They do not simply increase activity but change the enzyme's substrate specificity and kinetics, leading to a different, potentially more pathogenic, peptide repertoire.
Dominant Negative (DN)
No clear evidence for dominant-negative effects of ERAP1 variants has been established. ERAP1 functions as a monomer, and the impact of variants is generally considered in a co-dominant or additive manner, where the combined effect of both alleles determines the overall phenotype.
View complete mutation data：
Gene Ontology (GO)
| • aminopeptidase activity | • metallopeptidase activity |
| • zinc ion binding | • peptide binding |
| • endoplasmic reticulum | • proteolysis |
| • antigen processing and presentation of exogenous peptide antigen via MHC class I | • response to cytokine |
| • regulation of blood pressure |
Pathways
• Antigen processing and presentation (MHC class I)
• ER-associated degradation (ERAD) pathway
• Cytokine-cytokine receptor interaction
• Renin-angiotensin system
Protein Summary
ERAP1 is a 941-amino acid type II integral membrane protein anchored in the ER membrane. It consists of a short N-terminal cytoplasmic domain, a transmembrane domain, and a large luminal catalytic domain. The catalytic domain contains a HEXXH(X)18E zinc-binding motif characteristic of M1 aminopeptidases. The protein forms a large, closed 'funnel-like' structure that allows processive trimming of peptides from the N-terminus. It preferentially cleaves hydrophobic or aromatic amino acids and has a 'molecular ruler' mechanism that determines the final length of the peptide. ERAP1 is constitutively expressed in most tissues but is upregulated by interferons (IFN-γ). Its primary function is to generate final antigenic peptides for loading onto MHC class I molecules, a process crucial for CD8+ T-cell recognition. It also plays a role in shedding cell surface cytokine receptors and in the regulation of blood pressure.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| ERAP1 Knockout HEK293T Cell Line | EDJ-KQ152 | Human | 51752 | Details Get a Quote |
| ERAP1 Knockout HEK293 Cell Line | EDC90666 | Human | 51752 | Details Get a Quote |
| ERAP1 Knockout A-549 Cell Line | EDJ-KQ42771 | Human | 51752 | Details Get a Quote |
| ERAP1 Knockout HCT 116 Cell Line | EDJ-KQ42772 | Human | 51752 | Details Get a Quote |
| ERAP1 Knockout HeLa Cell Line | EDJ-KQ42773 | Human | 51752 | Details Get a Quote |
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