Abstract
The study of antiviral pathways to reveal methods for the effective response and clearance of virus is closely related to understanding interferon (IFN) signaling and its downstream target genes, IFN-stimulated genes. One of the key antiviral factors induced by IFNs, 2′-5′ oligoadenylate synthase (OAS), is a well-known molecule that regulates the early phase of viral infection by degrading viral RNA in combination with RNase L, resulting in the inhibition of viral replication. In this review, we describe OAS family proteins from a different point of view from that of previous reviews. We discuss not only RNase L-dependent (canonical) and -independent (noncanonical) pathways but also the possibility of the OAS family members as biomarkers for various diseases and clues to non-immunological functions based on recent studies. In particular, we focus on OASL, a member of the OAS family that is relatively less well understood than the other members. We will explain its anti- and pro-viral dual roles as well as the diseases related to single-nucleotide polymorphisms in the corresponding gene.
Highlights
To counter virus infection, the immune system produces antiviral cytokines
The antiviral activity of the oligoadenylate synthase (OAS) family and 2-5ARNase L is well characterized,[1,2,3] it was reported recently that not all of the OAS antiviral function is mediated by the RNase L-dependent pathway.[4,5]
Eight Oas[1] genes and one gene each for OAS2 and OAS3 exist on chromosome 8.10 Mice have two Oligoadenylate synthase-like (OASL) genes (Oasl[1] and Oasl2) on chromosome 5.11 Studies using genetically modified mouse models for the OAS genes may allow us to gain insights into the human OAS family functions, because the exon/intron structures of all the genes are conserved between humans and mice.[10]
Summary
The immune system produces antiviral cytokines. Interferon (IFN) is the most powerful antiviral cytokine, and it induces IFN-stimulated genes that mediate antiviral effector functions. Human OAS1 (hOAS1) has two spliced forms that produce proteins of 40 and 46 kDa, each containing a distinct C-terminal sequence.[7] Three more alternative splice forms of Oas[1] are generated by single-nucleotide polymorphisms (SNPs).[8] There are two isoforms of OAS2 (p69 and p71), and one 100 kDa OAS3 form.[7] Two isoforms of hOASL OASLa (p59) and OASLb (p30) are coded by a gene located on chromosome 12 (in the 12q24.2 region), but OASLa is the dominant isoform; OASLb has a C-terminal truncation Another OASL isoform, OASLd, which is strongly induced by IFNγ, was discovered.[9] In the mouse genome, eight Oas[1] genes and one gene each for OAS2 and OAS3 exist on chromosome 8.10 Mice have two OASL genes (Oasl[1] and Oasl2) on chromosome 5.11 Studies using genetically modified mouse models for the OAS genes may allow us to gain insights into the human OAS family functions, because the exon/intron structures of all the genes are conserved between humans and mice.[10] In this article, we review the immune-related and other cellular functions of OAS and the dual role of OASL. In Vero cells, hOASL expression increases the resistance against singlestranded RNA viruses, including picornavirus and encephalomyocarditis, but not against a DNA virus, herpes simplex virus 1.32 A recent study using an OASL deletion mutant
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