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Abstract
The importance of the IFN-induced oligoadenylate synthetase (OAS) proteins and the OAS/RNase L pathway in the innate response against viral pathogens is well-established, however the observed differences in anti-viral activity between the human OAS1 p46 and p42 isoforms are not fully understood. The protein expression of these isoforms is determined by the SNP rs10774671, either being an A or a G allele resulting in expression of either the p42 or the p46 isoform. Using fluorescence microscopy and immunoblot analysis of fractionated cell samples, we show here that the CaaX motif is of key importance to the cellular localization. The OAS1 p42 isoform is mainly located in the cytosol, whereas the p46 isoform with a C-terminal CaaX motif is translocated to membranous organelles, like the mitochondria. We furthermore observed differences between p42 and p46 in their effect on mitochondrial physiology using high resolution respirometry and fluorometry. Overexpression of OAS1 p42 and IFN-β treatment of HeLa cells (AA genotype) resulted in significantly increased respiration, which was not seen with p46 overexpression. The difference in subcellular localization and mitochondrial effect of these two OAS1 isoforms might help to explain the anti-viral mechanisms that differentiate these proteins.
Highlights
The oligoadenylate synthetase (OAS) family genes encode four different types of proteins: OAS1, OAS2, OAS3, and OAS-Like (OAS-L) of which the OAS1, OAS2, and OAS3 are enzymatically active while the OAS-L is not [1]
HeLa cells was increased by approximately two-fold after 48 hours of IFN-β treatment in three different respiration states, i.e., ROUTINE, LEAK, and electron transport system (ETS) (Figure 2A)
This results in a noncoupled mitochondrial state in which there are no limitations to proton availability thereby enabling the determination of the maximum capacity of the electron transport system (ETS)
Summary
The oligoadenylate synthetase (OAS) family genes encode four different types of proteins: OAS1, OAS2, OAS3, and OAS-Like (OAS-L) of which the OAS1, OAS2, and OAS3 are enzymatically active while the OAS-L is not [1]. The structure and mechanistic function of the OAS1 protein is well-described [2,3], as well as the canonical downstream anti-viral properties of the OAS-activated. The human OAS1 gene is 25,414 base pairs long and consists of eight exons. Of these exons, the first five exons from the 50 end are translated into the core protein while the latter three exons enable alternative splicing into the six known protein isoforms of OAS1. The first five exons from the 50 end are translated into the core protein while the latter three exons enable alternative splicing into the six known protein isoforms of OAS1 Two of these isoforms are the p42 and p46 variants which are the focus of this study.
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