Abstract
Following influenza infection, rs2248374-G ERAP2 expressing cells may transcribe an alternative spliced isoform: ERAP2/Iso3. This variant, unlike ERAP2-wt, is unable to trim peptides to be loaded on MHC class I molecules, but it can still dimerize with both ERAP2-wt and ERAP1-wt, thus contributing to profiling an alternative cellular immune-peptidome. In order to verify if the expression of ERAP2/Iso3 may be induced by other pathogens, PBMCs and MDMs isolated from 20 healthy subjects were stimulated with flu, LPS, CMV, HIV-AT-2, SARS-CoV-2 antigens to analyze its mRNA and protein expression. In parallel, Calu3 cell lines and PBMCs were in vitro infected with growing doses of SARS-CoV-2 (0.5, 5, 1000 MOI) and HIV-1BAL (0.1, 1, and 10 ng p24 HIV-1Bal/1 × 106 PBMCs) viruses, respectively. Results showed that: (1) ERAP2/Iso3 mRNA expression can be prompted by many pathogens and it is coupled with the modulation of several determinants (cytokines, interferon-stimulated genes, activation/inhibition markers, antigen-presentation elements) orchestrating the anti-microbial immune response (Quantigene); (2) ERAP2/Iso3 mRNA is translated into a protein (western blot); (3) ERAP2/Iso3 mRNA expression is sensitive to SARS-CoV-2 and HIV-1 concentration. Considering the key role played by ERAPs in antigen processing and presentation, it is conceivable that these enzymes may be potential targets and modulators of the pathogenicity of infectious diseases and further analyses are needed to define the role played by the different isoforms.
Highlights
IntroductionERAP1 and ERAP2 (endoplasmic reticulum aminopeptidases 1 and 2) are two IFNγ- and TNFα-inducible, ubiquitously-expressed human enzymes, which belong to the M1 family of zinc aminopeptidases [1]
ERAP1 and ERAP2 are two IFNγ- and TNFα-inducible, ubiquitously-expressed human enzymes, which belong to the M1 family of zinc aminopeptidases [1]
Based on the results recently reported by Ye and co-workers [19], we investigated if the expression of the recently characterized ERAP2/Iso3 is flu-specific or if it can be triggered by other microbial stimuli
Summary
ERAP1 and ERAP2 (endoplasmic reticulum aminopeptidases 1 and 2) are two IFNγ- and TNFα-inducible, ubiquitously-expressed human enzymes, which belong to the M1 family of zinc aminopeptidases [1]. In the endoplasmic reticulum (ER), ERAPs shape the antigenic repertoire by trimming the N-terminus of precursor peptides previously generated in the cytoplasm by the proteasome. In this way, ERAPs generate optimal-length peptides for loading onto MHC class I groove to be presented to CD8+ T lymphocytes [2,3]. ERAP1–ERAP2 heterodimer generation has been demonstrated to improve the shaping of peptides suitable for MHC class I molecule binding [5].
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