No association of type 1 diabetes with a functional polymorphism of the LRAP gene

Qu, Hui‐Qi; Marchand, Luc; Fréchette, Rosalie; Bertucci, François; Lü, Yang; Polychronakos, Constantin

doi:10.1016/j.molimm.2006.10.015

Cited by 3 publications

(1 citation statement)

References 15 publications

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“…These changes could alter the epitope repertoire presented, therefore leading to a defective immune response. No correlation between ERAP2 SNPs and enzymatic activity has been reported to date, but an ERAP2 genetic variation (rs2762) has been found to result to an eight-fold higher gene expression [103].…”

Section: Erap1/erap2 Polymorphisms In Auto-immunity and Cancermentioning

confidence: 94%

A New Role for Zn(II) Aminopeptidases: Antigenic Peptide Generation and Destruction

Evnouchidou

Papakyriakou²,

Stratikos

2009

CPD

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During the last few years a novel role for previously known Zn(II) aminopeptidases has emerged, attracting a great deal of scientific interest to these molecules. Aminopeptidases appear now to play a key role in the last, yet crucial, proteolytic steps that generate small peptides for presentation onto MHC class I molecules so that the mature MHC-peptide complexes can be recognized by cytotoxic T-lymphocytes. In that context, ER aminopeptidases have been shown to strongly affect the adaptive immune response. ER aminopeptidase 1 (ERAP1) has been demonstrated to be a critical determinant of the immune response by generating mature antigenic epitopes from peptide precursors that arrive into the ER originating primarily from intracellular proteins degraded by the proteasome. At least one more related aminopeptidase, renamed ERAP2, appears to have important yet distinct roles in antigenic peptide generation. This review discusses recent findings that help to unravel the role of ER aminopeptidases in the immune response as well as the molecular properties that underlie this role. Determining the exact role and mechanism of action of these aminopeptidases will potentially provide tools for the pharmaceutical manipulation of the immune response on a subtle and qualitative level leading to novel therapeutic opportunities for the treatments of diseases ranging from autoimmunity to cancer.

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Section: Erap1/erap2 Polymorphisms In Auto-immunity and Cancermentioning

confidence: 94%

A New Role for Zn(II) Aminopeptidases: Antigenic Peptide Generation and Destruction

Evnouchidou

Papakyriakou²,

Stratikos

2009

CPD

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The role of endoplasmic reticulum aminopeptidases in type 1 diabetes mellitus

et al. 2023

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Balancing Selection Maintains a Form of ERAP2 that Undergoes Nonsense-Mediated Decay and Affects Antigen Presentation

et al. 2010

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A remarkable characteristic of the human major histocompatibility complex (MHC) is its extreme genetic diversity, which is maintained by balancing selection. In fact, the MHC complex remains one of the best-known examples of natural selection in humans, with well-established genetic signatures and biological mechanisms for the action of selection. Here, we present genetic and functional evidence that another gene with a fundamental role in MHC class I presentation, endoplasmic reticulum aminopeptidase 2 (ERAP2), has also evolved under balancing selection and contains a variant that affects antigen presentation. Specifically, genetic analyses of six human populations revealed strong and consistent signatures of balancing selection affecting ERAP2. This selection maintains two highly differentiated haplotypes (Haplotype A and Haplotype B), with frequencies 0.44 and 0.56, respectively. We found that ERAP2 expressed from Haplotype B undergoes differential splicing and encodes a truncated protein, leading to nonsense-mediated decay of the mRNA. To investigate the consequences of ERAP2 deficiency on MHC presentation, we correlated surface MHC class I expression with ERAP2 genotypes in primary lymphocytes. Haplotype B homozygotes had lower levels of MHC class I expressed on the surface of B cells, suggesting that naturally occurring ERAP2 deficiency affects MHC presentation and immune response. Interestingly, an ERAP2 paralog, endoplasmic reticulum aminopeptidase 1 (ERAP1), also shows genetic signatures of balancing selection. Together, our findings link the genetic signatures of selection with an effect on splicing and a cellular phenotype. Although the precise selective pressure that maintains polymorphism is unknown, the demonstrated differences between the ERAP2 splice forms provide important insights into the potential mechanism for the action of selection.

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No association of type 1 diabetes with a functional polymorphism of the LRAP gene

Cited by 3 publications

References 15 publications

A New Role for Zn(II) Aminopeptidases: Antigenic Peptide Generation and Destruction

A New Role for Zn(II) Aminopeptidases: Antigenic Peptide Generation and Destruction

The role of endoplasmic reticulum aminopeptidases in type 1 diabetes mellitus

Balancing Selection Maintains a Form of ERAP2 that Undergoes Nonsense-Mediated Decay and Affects Antigen Presentation

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