The p59 oligoadenylate synthetase-like protein possesses antiviral activity that requires the C-terminal ubiquitin-like domain

Abstract

Viral infection of mammalian cells prompts the innate immune system to initiate an antiviral response. The recognition of the virus triggers several antiviral signalling pathways, which among others include the family of 29-59 oligoadenylate synthetase (OAS) proteins. The p59 protein encoded by the OAS-like (OASL) gene is an atypical member of the OAS family in the sense that it lacks the characteristic 29-59 oligoadenylate synthetase activity. We decided to investigate the putative antiviral activity of p59 by ectopically expressing this protein in Vero cells and then infecting these cells with virus. We demonstrate that OASL has an antiviral effect against the single-stranded RNA virus picornavirus, encephalomyocarditis virus, but not against a large DNA virus, herpes simplex virus 1. Importantly, this antiviral activity was lost in a truncated version of p59 lacking the ubiquitin-like C-terminal domain of p59. Taken together our results indicate that p59 is indeed an antiviral protein that works through a novel mechanism distinct from other OAS proteins.Interferons (IFN) are signalling molecules that constitute an important part of the vertebrate innate immune system (Stark et al., 1998). IFN induce an antiviral state via binding to their cognate receptor present on the cell surface. Receptor engagement triggers a signalling cascade mediated by Janus kinases (Jak) and signal tranducers and activators of transcription (STAT) that leads to the transcription of hundreds of genes (Der et al., 1998). For the majority of IFN-induced proteins (ISGs), the downstream mechanism by which they inhibit viral replication is poorly understood. Nevertheless, for a few selected ISGs there is some understanding of the mechanism by which they block viral replication. For example, the double-stranded (ds) RNAactivated protein kinase (PKR) (Williams, 1999) and the p56 protein (Guo et al., 2000) inhibit translation in virusinfected cells by preventing initiation of protein synthesis. The family of 29-59 oligoadenylate synthetase proteins (OAS) target translation indirectly via activation of a latent RNase (RNase L) that degrades both mRNA and rRNA in infected cells (Justesen et al., 2000).The OAS proteins were originally discovered as dsRNAinduced inhibitors of protein synthesis (Hovanessian et al., 1977;Roberts et al., 1976). The activity of OAS proteins is under strict control. While the transcription of the OAS gene family is induced by IFN, the translated proteins are latent enzymes that require dsRNA for activation. The activation of the OAS enzymes results in the synthesis of 29-59-linked oligoadenylates (2-5A) from ATP (Justesen et al., 2000). In turn, these 2-5A can bind to RNase L, which subsequently dimerizes into its active form. Activated RNase L then degrades viral and cellular RNAs suppressing protein synthesis and viral growth (Dong & Silverman, 1995 In humans, the OAS gene family is composed of four genes located on chromosome 12. The OAS1, OAS2 and OAS3 genes are encoded by a tightly coupled locus on 12q24.1 and t...

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