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

BMC Cell Biology

Pia Møller Martensen²  Just Justesen²  Erik Ilsø Christensen¹  Jesper Buchhave Poulsen²  Mariann Fagernæs Hansen²  Jytte Pahus²  Karina Hansen Kjær² 

[1] Department of Biomedicine, Aarhus University, Wilhelm Meyers Allé 3, 8000 Aarhus C, Denmark;Department of Molecular Biology and Genetics, Aarhus University, C.F. Møllers Allé 3, 8000 Århus C, Denmark

关键词: Diabetes;    Mitochondria;    Single Nucleotide Polymorphism (SNP);    2'-5' Oligoadenylate Synthetase (OAS);   

Others  :  1088723
DOI  :  10.1186/1471-2121-15-33

 received in 2014-04-16, accepted in 2014-08-29,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Kjær et al.; licensee BioMed Central Ltd.

【 图 表 】

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