ERAP2

What is ERAP2 protein?

ERAP2 (endoplasmic reticulum aminopeptidase 2) gene is a protein coding gene which situated on the long arm of chromosome 5 at locus 5q15. This gene encodes a zinc metalloaminopeptidase of the M1 protease family that resides in the endoplasmic reticulum and functions in N-terminal trimming antigenic epitopes for presentation by major histocompatibility complex (MHC) class I molecules. The ERAP2 protein is consisted of 960 amino acids and its molecular mass is approximately 110.5 kDa.

What is the function of ERAP2 protein?

ERAP2 is a zinc metalloproteinase localized in the endoplasmic reticulum, which is mainly involved in the processing and presentation of antigenic peptides. It plays a key role in immune response by cutting and trimming peptide segments to make them suitable for binding to Major histocompatibility complex (MHC) Class I molecules. In addition, ERAP2 is involved in regulating the expression of receptors and signaling molecules on the cell surface, influencing a variety of biological processes such as angiogenesis, inflammatory response, and tumorigenesis.

ERAP2 Related Signaling Pathway

ERAP2 is involved in several signaling pathways related to immune response. It influences the antigen peptide library presented by MHC Class I molecules through precise pruning of antigenic peptides, thereby regulating T cell-mediated immune responses. ERAP2 activity can influence the activation of natural killer cells (NK cells) and CD8+ T cells, which in turn involves natural killer cell-mediated cytotoxicity pathways and T cell receptor (TCR) signaling pathways.

ERAP2 Related Diseases

ERAP2 has also been implicated in the development of a variety of inflammatory and autoimmune diseases, such as the pathogenesis of inflammatory arthritis syndroms such as ankylosing spondylitis and preeclampsia. In the tumor microenvironment, the expression and function of ERAP2 are also correlated with the level of immune cell infiltration, which may influence tumor immune escape and the effect of immunotherapy by regulating the presentation of tumor-associated antigens.

Fig1. Illustration of ERAP2 immune evasion or anti-tumor cytotoxic mechanism hypothesis. (Michelle D Warthan, 2018)

Bioapplications of ERAP2

In terms of clinical application, ERAP2 research helps to predict the prognosis and response to specific chemotherapy drugs in certain cancer patients. For example, studies have shown that high expression of ERAP2 is significantly associated with better survival in patients with squamous cell lung cancer (SqCLC) and is positively associated with immune cell infiltration, suggesting that ERAP2 may serve as a potential biomarker and immunotherapeutic target. In addition, the genetic polymorphism of ERAP2 is associated with disease susceptibility in different populations, which has important significance in personalized medicine and precision therapy.

Case Study 1: Karin Schmidt, 2023

The therapy of cancer by adoptive T cell transfer (ACT) requires T cell receptors (TCRs) with optimal affinity for HLA class I-bound peptides (pHLA-I). But not every patient responds to ACT. Therefore, it is critical to understand the individual factors influencing the recognition of HLA class I-bound peptides (pHLA-I) by TCRs. Focusing on three immunotherapy-targeted human HLA-A* 02:01-presented T cell epitopes we investigated the contribution of the ER-resident aminopeptidases ERAP1 and ERAP2 to TCR recognition of cancer cells. The results showed that ERAP2 on its own, when expressed in ERAP-deficient cells, elicited a strong CTL response towards the Tyrosinase368-376 epitope. In vitro generated TAP-dependent N-terminally extended epitope precursor peptides were differently customized by ERAP1 and ERAP2. ERAP2 also influenced recognition of the gp100209-217 tumor epitope and enhanced T cell recognition of the MART-126/27-35 epitope in the absence of ERAP1 expression.

Fig1. ERAP2-dependent T cell recognition of HLA-A* 0201-gp100209–217.

Fig2. ERAP2-dependent T cell recognition of HLA-A* 0201-MART126/27–35 by the lower-affinity TCR DMF4.

Case Study 2: Pian Yu, 2022

Pancreatic cancer is one of the most malignant tumors, with rapid metastasis, high mortality rate, and difficult early screening. It is particularly important to further identify biomarkers associated with gemcitabine resistance to improve the sensitivity of gemcitabine treatment. Drug sensitivity data and the corresponding transcript data derived from the Genomics of Drug Sensitivity in Cancer (GDSC) database for correlation analysis was adopted to obtain genes related to gemcitabine sensitivity. Moreover, the survival model of pancreatic cancer patients treated with gemcitabine in The Cancer Genome Atlas (TCGA) database was utilized to obtain key genes. Multiple in vitro assays were performed to verify the function of the key biomarker. Endoplasmic Reticulum Aminopeptidase 2 (ERAP2) was identified as a biomarker promoting gemcitabine resistance, and its high expression resulted in a worse prognosis. Besides, gemcitabine significantly increased the mRNA and protein levels of ERAP2 in pancreatic cancer cells. Additionally, ERAP2 knockdown suppressed tumorigenesis and potentiated gemcitabine-induced growth, migration and invasion inhibition in human pancreatic cancer cells.

Fig3. The Protein levels of ERAP2 in BxPC-3 and PANC-1 cell lines treated with gemcitabine were assessed by western blot.

Fig4. Cell proliferation assay in two pancreatic cancer cell lines treated with ERAP2 knockdown, gemcitabine alone or gemcitabine with ERAP2 knockdown.

ERAP2 has several biochemical functions, for example, aminopeptidase activity,metalloaminopeptidase activity,metallopeptidase activity. Some of the functions are cooperated with other proteins, some of the functions could acted by ERAP2 itself. We selected most functions ERAP2 had, and list some proteins which have the same functions with ERAP2. You can find most of the proteins on our site.

ERAP2 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with ERAP2 here. Most of them are supplied by our site. Hope this information will be useful for your research of ERAP2.

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