Mitochondrial localization of the OAS1 p46 isoform associated with a common single nucleotide polymorphism

Karina Hansen Kjær, Jytte Pahus, Mariann Fagernæs Hansen, Jesper Buchhave Poulsen, Erik Ilsø Christensen, Just Justesen, Pia Møller Martensen

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Abstract

Abstract
Background: The expression of 2′-5′-Oligoadenylate synthetases (OASs) is induced by type 1 Interferons (IFNs) in
response to viral infection. The OAS proteins have a unique ability to produce 2′-5′ Oligoadenylates, which bind
and activate the ribonuclease RNase L. The RNase L degrades cellular RNAs which in turn inhibits protein translation
and induces apoptosis. Several single nucleotide polymorphisms (SNPs) in the OAS1 gene have been associated
with disease. We have investigated the functional effect of two common SNPs in the OAS1 gene. The SNP
rs10774671 affects splicing to one of the exons in the OAS1 gene giving rise to differential expression of the OAS1
isoforms, and the SNP rs1131454 (former rs3741981) resides in exon 3 giving rise to OAS1 isoforms with either a
Glycine or a Serine at position 162 in the core OAS unit.
Results: We have used three human cell lines with different genotypes in the OAS1 SNP rs10774671, HeLa cells
with the AA genotype, HT1080 cells with AG, and Daudi cells with GG. The main OAS1 isoform expressed in Daudi
and HT1080 cells was p46, and the main OAS1 isoform expressed in HeLa cells was p42. In addition, low levels of
the OAS1 p52 mRNA was detected in HeLa cells and p48 mRNA in Daudi cells, and trace amounts of p44a mRNA
were detected in the three cell lines treated with type 1 interferon. We show that the OAS1 p46 isoform was
localized in the mitochondria in Daudi cells, whereas the OAS1 isoforms in HeLa cells were primarily localized in
cytoplasmic vacuoles/lysosomes. By using recombinantly expressed OAS1 mutant proteins, we found that the OAS1
SNP rs1131454 (former rs3741981) did not affect the enzymatic OAS1 activity.
Conclusions: The SNP rs10774671 determines differential expression of the OAS1 isoforms. In Daudi and HT1080
cells the p46 isoform is the most abundantly expressed isoform associated with the G allele, whereas in HeLa cells
the most abundantly expressed isoform is p42 associated with the A allele. The SNP rs1131454 (former rs3741981)
does not interfere with OAS1 enzyme activity. The OAS1 p46 isoform localizes to the mitochondria, therefore a full
2-5A system can now be found in the mitochondria.
OriginalsprogEngelsk
Artikelnummer1
TidsskriftB M C Cell Biology
Vol/bind15
Udgave nummer33
Antal sider14
ISSN1471-2121
DOI
StatusUdgivet - 2014

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