ICP0 Prevents RNase L-Independent rRNA Cleavage in Herpes Simplex Virus Type 1-Infected Cells

Abstract

The classical interferon (IFN)-dependent antiviral response to viral infection involves the regulation of IFN-stimulated genes (ISGs), one being the gene encoding cellular endoribonuclease RNase L, which arrests protein synthesis and induces apoptosis by nonspecifically cleaving rRNA. Recently, the herpes simplex virus type 1 (HSV-1) protein ICP0 has been shown to block the induction of ISGs by subverting the IFN pathway upstream of the 2-5-oligoadenylate synthetase (OAS)/RNase L pathway. We report that ICP0 also prevents rRNA degradation at late stages of HSV-1 infection, independent of its E3 ubiquitin ligase activity, and that the resultant rRNA degradation is independent of the classical RNase L antiviral pathway. Moreover, the degradation is independent of the viral RNase vhs and is independent of IFN response factor 3. These studies indicate the existence of another, previously unidentified, RNase that is part of the host antiviral response to viral infection.Viral infection of mammalian cells induces a robust antiviral response intended to restrict viral replication and propagation. A predominant characteristic of this innate immune response is the expression and secretion of interferons (IFNs), a family of immunomodulatory cytokines with antiviral and antiproliferative activities (43). Once secreted from infected cells, the type I IFNs (alpha IFN [IFN-␣] and IFN-␤) bind to their cognate class II cytokine receptors in both paracrine and autocrine fashions and induce the phosphorylation of Jak/Stat molecules, leading to the nuclear translocation of activated Stat1-Stat2-IRF9 heterotrimers. These complexes bind to the IFN-stimulated response elements (ISRE) in promoters of IFN-stimulated genes (ISGs), resulting in the robust induction of these antiviral effector molecules. Among the ISGs most intently studied are the double-stranded RNA (dsRNA)-dependent protein kinase R (PKR), which induces protein synthesis arrest (52), and the ubiquitous 2Ј-5Ј-oligoadenylate synthetase (OAS) family of proteins, which function to promote RNA degradation (44). Once upregulated, PKR and OAS become activated by binding to dsRNA, a by-product of viral replication.OAS catalyzes the synthesis of variable short 2Ј-5Ј-linked oligoadenylates (2Ј-5ЈA) from ATP, which in turn activate the latent endoribonuclease RNase L to cleave cellular and viral RNA (36). Infection with several viruses, including vaccinia virus and encephalomyocarditis virus, leads to RNase L-dependent rRNA degradation (44). Ultimately, rRNA cleavage results in protein synthesis inhibition and apoptosis and constitutes a significant cellular antiviral event to prevent viral propagation (7). Indeed, several viruses have evolved specific mechanisms to counteract the 2Ј-5ЈA pathway, including human immunodeficiency virus type 1, vaccinia virus, and the alphaherpesvirus herpes simplex virus type 1 (HSV-1) (8, 27, 53). HSV-1 infection of conjunctival cells induces the synthesis of 2Ј-5ЈA derivatives, which antagonize RNase L activation by competing with genuine 2Ј-5ЈA...

Herpes simplex virus-infected cell protein 0 blocks the silencing of viral DNA by dissociating histone deacetylases from the CoREST–REST complex

“…First, ICP0 blocks IFN-dependent host responses designed to block viral replication (15)(16)(17)(18). Second, it is a promiscuous transactivator of genes introduced by infection or transfection (6)(7)(8).…”

Control of Herpes Simplex Virus Replication Is Mediated through an Interferon Regulatory Factor 3-Dependent Pathway

“…UV-inactivated HSV-1 induces IRF-3 dimerization and activation, leading to IFN induction, suggesting that very early events in infection are responsible for triggering this cascade in the absence of viral gene expression (6,23). ICP0, an immediate-early gene of HSV-1, interacts with IRF-3 and plays a critical role in preventing the induction of the IFN response (10,23,27,28,30,42). Additional HSV genes such as the virion host shutoff protein, ICP34.5, and ICP27 also interfere with the activity of IRF-3 (23,26,48).…”

Degradation of rRNA in BM-N cells from the silkworm Bombyx mori during abortive infection with heterologous nucleopolyhedroviruses

“…Thus, NPV-infected B. mori cells represent an excellent model system to study and gain a greater understanding of antiviral strategies of lepidopteran insects. Furthermore, in-depth characterization of the rRNA cleavage and degradation events in NPV-infected B. mori cells is expected to give evolutionary insight into the antiviral mechanisms underlying rRNA cleavage and degradation, including both RNase L-dependent (interferon-regulated 2-5A system) and RNase L-independent pathways, in virus-infected mammalian cells (Banerjee et al, 2000;Liang et al, 2006;Silverman, 2007;Sobol & Mossman, 2006).…”