A New ERAP2/Iso3 Isoform Expression Is Triggered by Different Microbial Stimuli in Human Cells. Could It Play a Role in the Modulation of SARS-CoV-2 Infection?

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.

Genome-wide bioinformatic analyses predict key host and viral factors in SARS-CoV-2 pathogenesis

“…Aberrant isoform usage and splicing have previously been associated with the human antiviral response, cancer, and neurodegenerative diseases 64 – 66 ; moreover, a recent study found that SARS-CoV-2 infection alters isoform usage of the ERAP2 gene 67 . However, to our knowledge, ours is the first genome-wide analysis of the effect of SARS-CoV-2 on isoform usage.…”

Polymorphisms of Antigen-Presenting Machinery Genes in Non-Small Cell Lung Cancer: Different Impact on Disease Risk and Clinical Parameters in Smokers and Never-Smokers

“…rs2248374A allele gives normal ERAP2 protein expression, whereas rs2248374G produces unstable mRNA degraded by nonsense mediated decay and usually results in undetectable protein expression (56). However, it has been reported recently that during stimulation by microbial infections the rs2248374G allele may give two truncated protein isoforms absent in rs2248374AA homozygotes and with an unknown biological role (57)(58)(59), possibly interfering in ERAP1 activity. Why the haplotype GCTCCG without functional ERAP2 molecule gives opposite results in never-smokers versus smokers, whereas the same ERAP1 (GCTCCA) with functional ERAP2 does not affect NSCLC prevalence in any of these groups, is not clear.…”

Antigen presentation in SARS-CoV-2 infection: the role of class I HLA and ERAP polymorphisms

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