An allelic variant in the intergenic region between ERAP1 and ERAP2 correlates with an inverse expression of the two genes

Paladini, Fabiana; Fiorillo, Maria Teresa; Vitulano, Carolina; Tedeschi, Valentina; Piga, Matteo; Cauli, Alberto; Mathieu, Alessandro; Sorrentino, Rosa

doi:10.1038/s41598-018-28799-8

Cited by 36 publications

(34 citation statements)

References 60 publications

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“…In a recent study a polymorphism located in the ERAP2 promoter region, rs7586269, was associated with opposite changes in the expression of ERAP1 and ERAP2, so that decreased expression of ERAP2 correlated with increased ERAP1 expression, suggesting a concerted regulation of the expression of both genes by this SNP ( 67 ). Yet, unlike rs2248374 and rs10044354, the minor allele frequency of rs7586269 is rather low in most populations.…”

Section: Erap2 Polymorphism and Expressionmentioning

confidence: 99%

How ERAP1 and ERAP2 Shape the Peptidomes of Disease-Associated MHC-I Proteins

2018

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Four inflammatory diseases are strongly associated with Major Histocompatibility Complex class I (MHC-I) molecules: birdshot chorioretinopathy (HLA-A*29:02), ankylosing spondylitis (HLA-B*27), Behçet's disease (HLA-B*51), and psoriasis (HLA-C*06:02). The endoplasmic reticulum aminopeptidases (ERAP) 1 and 2 are also risk factors for these diseases. Since both enzymes are involved in the final processing steps of MHC-I ligands it is reasonable to assume that MHC-I-bound peptides play a significant pathogenetic role. This review will mainly focus on recent studies concerning the effects of ERAP1 and ERAP2 polymorphism and expression on shaping the peptidome of disease-associated MHC-I molecules in live cells. These studies will be discussed in the context of the distinct mechanisms and substrate preferences of both enzymes, their different patterns of genetic association with various diseases, the role of polymorphisms determining changes in enzymatic activity or expression levels, and the distinct peptidomes of disease-associated MHC-I allotypes. ERAP1 and ERAP2 polymorphism and expression induce significant changes in multiple MHC-I-bound peptidomes. These changes are MHC allotype-specific and, without excluding a degree of functional inter-dependence between both enzymes, reflect largely separate roles in their processing of MHC-I ligands. The studies reviewed here provide a molecular basis for the distinct patterns of genetic association of ERAP1 and ERAP2 with disease and for the pathogenetic role of peptides. The allotype-dependent alterations induced on distinct peptidomes may explain that the joint association of both enzymes and unrelated MHC-I alleles influence different pathological outcomes.

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Section: Erap2 Polymorphism and Expressionmentioning

confidence: 99%

How ERAP1 and ERAP2 Shape the Peptidomes of Disease-Associated MHC-I Proteins

2018

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“…This is also suggested by the association of ERAP2 with a wider array of diseases, such as preeclampsia or IBD ( 36 – 38 ). At present, the relationship between ERAP1 and ERAP2 is not completely clear: there are suggestions that they can cooperate, but also that ERAP2 can regulate ERAP1 expression and activity ( 39 , 40 ), modifying the peptidome and, consequently, the expression of the HLA molecules in a subtype-dependent manner ( 23 ). LNPEP has been involved in diabetes ( 41 ) and associated with psoriasis ( 42 , 43 ), sharing the last feature with the other two aminopeptidases.…”

Section: Disease Associationsmentioning

confidence: 99%

“…A second implication is that the redundancy of their function can lead to a “quantitative” control of the three aminopeptidases so that the full expression of all of them is disfavored. In this regard, we have recently shown that the transcription of ERAP1 and ERAP2 is interlinked: the variant G at rs75862629 in the intergenic region between the two genes strongly influences the expression of the two aminopeptidases with a down-modulation of ERAP2 coupled with a significant higher expression of ERAP1 ( 40 ). Even more intriguing is the observation that the ERAP2 variants co-segregating with a lower or null expression of ERAP2 (G at rs75862629 and G at rs2248374, respectively) appear more frequent in the equatorial regions, where the malaria has been endemic.…”

Section: Do the Three Aminopeptidases Have An Extracellular Role?mentioning

confidence: 99%

The Multifaceted Nature of Aminopeptidases ERAP1, ERAP2, and LNPEP: From Evolution to Disease

et al. 2020

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In the human genome, the aminopeptidases ERAP1, ERAP2 and LNPEP lie contiguously on chromosome 5. They share sequence homology, functions and associations with immune-mediated diseases. By analyzing their multifaceted activities as well as their expression in the zoological scale, we suggest here that the progenitor of the three aminopeptidases might be LNPEP from which the other two aminopeptidases could have derived by gene duplications. We also propose that their functions are partially redundant. More precisely, the evolutionary story of the three aminopeptidases might have been dictated by their role in regulating the renin–angiotensin system, which requires their controlled and coordinated expression. This hypothesis is supported by the many species that lack one or the other gene as well as by the lack of ERAP2 in rodents and a null expression in 25% of humans. Finally, we speculate that their role in antigen presentation has been acquired later on during evolution. They have therefore been diversified between those residing in the ER, ERAP1 and ERAP2, whose role is to refine the MHC-I peptidomes, and LNPEP, mostly present in the endosomal vesicles where it can contribute to antigen cross-presentation or move to the cell membrane as receptor for angiotensin IV. Their association with autoinflammatory/autoimmune diseases can therefore be two-fold: as “contributors” to the shaping of the immune-peptidomes as well as to the regulation of the vascular response.

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“…On the other hand, individuals who are homozygous for the A-allele present about 50% more enzyme in comparison to individuals with the heterozygous haplotype, suggesting that rs2248374 may be a marker of ERAP2 protein expression. Taking this into account, this study suggests that the A-allele for this SNP may be associated with increased expression of ERAP2 in HCV chronically infected individuals, therefore affecting the antigen presentation process and leading to a greater risk of susceptibility to HCV chronicity [36]. In addition, given the role of ERAP2 as a promoter of ERAP1 activity-through the formation of heterodimers with increased trimming efficacy-it has been observed that combination of rs26618-C/rs2248374-A on the two genes also provides a greater risk of susceptibility to HCV chronicity in Han Chinese population [46].…”

Section: Eraps and Hepatitis C Virus (Hcv)mentioning

confidence: 92%

“…Another polymorphism with a considerable effect on ERAP2 protein expression is rs10044354 (C/T), where homozygosity for the C allele results in very decreased levels of ERAP2 [34,35]. Recently, a study associated the polymorphism rs75862629 (A/G) in the promoter region of the ERAP2 gene with changes in the expression of ERAP2 and ERAP1 in the Sardinian population [36]. In particular, the G allele of rs7586269 resulted in a decreased ERAP2 protein expression and a higher ERAP1 expression, suggesting the possibility of a concerted regulation of the expression of both genes by this polymorphism.…”

Section: Erap2 Genetic Variantsmentioning

confidence: 99%

An Overview on ERAP Roles in Infectious Diseases

Saulle

Vicentini

Clerici

et al. 2020

Cells

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Endoplasmic reticulum (ER) aminopeptidases ERAP1 and ERAP2 (ERAPs) are crucial enzymes shaping the major histocompatibility complex I (MHC I) immunopeptidome. In the ER, these enzymes cooperate in trimming the N-terminal residues from precursors peptides, so as to generate optimal-length antigens to fit into the MHC class I groove. Alteration or loss of ERAPs function significantly modify the repertoire of antigens presented by MHC I molecules, severely affecting the activation of both NK and CD8 + T cells. It is, therefore, conceivable that variations affecting the presentation of pathogen-derived antigens might result in an inadequate immune response and onset of disease. After the first evidence showing that ERAP1-deficient mice are not able to control Toxoplasma gondii infection, a number of studies have demonstrated that ERAPs are control factors for several infectious organisms. In this review we describe how susceptibility, development, and progression of some infectious diseases may be affected by different ERAPs variants, whose mechanism of action could be exploited for the setting of specific therapeutic approaches.

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An allelic variant in the intergenic region between ERAP1 and ERAP2 correlates with an inverse expression of the two genes

Cited by 36 publications

References 60 publications

How ERAP1 and ERAP2 Shape the Peptidomes of Disease-Associated MHC-I Proteins

How ERAP1 and ERAP2 Shape the Peptidomes of Disease-Associated MHC-I Proteins

The Multifaceted Nature of Aminopeptidases ERAP1, ERAP2, and LNPEP: From Evolution to Disease

An Overview on ERAP Roles in Infectious Diseases

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