ERAP1: a potential therapeutic target for a myriad of diseases

ABSTRACT

Introduction: Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) is a key regulator of the peptide repertoire displayed by Major Histocompatibility Complex I (MHC I) to circulating CD8 + T cells and NK cells. Studies have highlighted the essential requirement for the generation of stable peptide MHC I in regulating both innate and adaptive immune responses in health and disease.

Areas covered: We review the role of ERAP1 in peptide trimming of N-terminally extended precursors that enter the ER, before loading on to MHC I, and the consequence of loss or downregulation of this activity. Polymorphisms in ERAP1 form multiple combinations (allotypes) within the population, and we discuss the contribution of this ERAP1 variation, and expression, on disease pathogenesis, including the resulting effect on both innate and adaptive immunity. We consider the current efforts to design inhibitors based on approaches using rational design and small molecule screening, and the potential effect of pharmacological modulation on the treatment of autoimmunity and cancer.

Expert opinion: ERAP1 is fundamental for the regulation of immune responses, through generation of the presented peptide repertoire at the cell surface. Modulation of ERAP1 function, through design of inhibitors, may serve as a vital tool for changing immune responses in disease.

KEYWORDS:

• ERAP1
• antigen processing and presentation
• MHC I
• CD8+ T cells
• NK cells
• cancer
• autoimmunity

Article Highlights

• Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) is a key regulator of peptide repertoire displayed at the cell surface, by trimming N-terminally extended peptides to the optimal length (8-10amino acids) for MHC I binding and presentation.

• Alterations in ERAP1 activity significantly alter the quality and quantity of the peptide repertoire, which can induce robust T cell or NK cell responses.

• ERAP1 is polymorphic within the population, and polymorphisms affect the function of ERAP1 activity.

• ERAP1 and ERAP2 polymorphic variants are associated with autoimmune conditions and cancer and has been shown to destroy immunogenic peptides associated with melanoma and murine colorectal carcinoma.

• Modulation of ERAP1, either by siRNA or pharmacological inhibition, has shown significant alterations in peptide repertoire, as well as tumour rejection in lymphoma and colorectal carcinoma models.

This box summarizes key points contained in the article.

Declaration of interest

E James sits on the advisory panel for Grey wolf Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded; however, E Reeves is supported by Cancer Research UK Programme Grant A16997.