NF-kappaB and virus infection: who controls whom

Abstract

Among the different definitions of viruses, 'pirates of the cell' is one of the most picturesque, but also one of the most appropriate. Viruses have been known for a long time to utilize a variety of strategies to penetrate cells and, once inside, to take over the host nucleic acid and protein synthesis machinery to build up their own components and produce large amounts of viral progeny. As their genomes carry a minimal amount of information, encoding only a few structural and regulatory proteins, viruses are largely dependent on their hosts for survival; however, despite their apparent simplicity, viruses have evolved different replicative strategies that are regulated in a sophisticated manner. During the last years, the study of the elaborate relationship between viruses and their hosts has led to the understanding of how viral pathogens not only are able to alter the host metabolism via their signaling proteins, but are also able to hijack cellular signaling pathways and transcription factors, and control them to their own advantage. In particular, the nuclear factor-kappaB (NF-kappaB) pathway appears to be an attractive target for common human viral pathogens. This review summarizes what is known about the control of NF-kappaB by viruses, and discusses the possible outcome of NF-kappaB activation during viral infection, which may benefit either the host or the pathogen.

Fig. 1. The NF-κB pathway. NF-κB heterodimers (p50/RelA) are sequestered in the cytoplasm by IκB inhibitory proteins (IκBα). Stimulation by stress-inducing agents, or exposure to inflammatory cytokines, mitogens or a diverse array of bacterial and viral pathogens leads to the activation of signaling cascades converging on the IKK complex. Phosphorylation of IκBα by activated IKK is a signal for its ubiquitylation and proteasome-dependent degradation. Freed NF-κB dimers translocate to the nucleus where they bind to κB elements and activate the transcription of a variety of genes involved in the control of cell proliferation and survival, in the inflammatory and immune response, as well as autoregulatory genes, including IκBα itself. Signaling pathways are described in the text.

Fig. 2. Different strategies of NF-κB activation by viruses. Some examples of different mechanisms of NF-κB activation by viruses are shown. Viral envelope glycoproteins (HIV gp120 and EBV gp350) activate signaling through engagement of cellular receptors (CD4 and CD21). Accumulation of viral dsRNA activates PKR, which in turn stimulates IKK. ER overload caused by massive viral glycoprotein production (influenza virus hemagglutinin HA; adenovirus E3 protein) leads to NF-κB activation possibly via calcium- or oxidative radical (ROI)-regulated signals. Distinct viral proteins encoded by HCV, RRV (rotavirus), EBV, HBV, HTLV-1 and HIV-1 activate NF-κB by interacting with different cellular signaling pathways.

Fig. 3. NF-κB in HSV-1 infection. HSV-1 activates NF-κB in a biphasic way. The first rapid and transient wave of activation (phase I) is thought to be triggered by the binding of the gD envelope glycoprotein to the herpesvirus entry mediator A (HveA), a member of the TNFR superfamily, whose cytoplasmic region binds to TRAFs, activating NF-κB. At later stages of infection (3–4 h post-infection), a second IKK-mediated wave of NF-κB activation dependent on synthesis of immediate early (IE) viral proteins is initiated (phase II), which leads to persistent activation of the factor. Persistent NF-κB activation results in the enhancement of the transcriptional activity of cellular and/or viral genes containing κB consensus sequences in their promoters. The lower panel represents the level of NF-κB DNA-binding activity in HSV-1-infected human keratinocytes, as determined by gel shift analysis of protein extracts at different times post-infection (p.i.) and quantified by Molecular Dynamics Phosphorimager analysis. Data are expressed as fold induction of the levels detected in uninfected control cells.

Fig. 4. Effect of inhibition of IKK activity on HSV-1 replication. (A) Structure of PGA₁. PGA₁ and other cyclopentenone prostanoids possess a reactive α,β-unsaturated carbonyl group in the cyclopentane ring which is responsible for binding and inactivating the β-subunit of the IKK complex, resulting in the block of NF-κB activation. (B) PGA₁ treatment (30 µM) inhibits HSV-1-induced IKK and NF-κB activity, and prevents IκBα degradation in HEp-2 cells. At 7 and 11 h after infection (p.i.), whole-cell extracts were analyzed for endogenous IKK activity and recovery by kinase assay (KA) and immunoblotting (IB), respectively (top panels), for IκBα degradation by immunoblot analysis (middle panel), and for NF-κB activation by gel shift analysis (bottom panel). (C) In HSV-1-infected HEp-2 cells, PGA₁ treatment causes a reduction in the levels of viral mRNA (ICP4, determined by northern blot analysis at 8 h p.i., upper panel), and of viral proteins (determined by western blot analysis, medium panel) and virus yield (determined by CPE_50% assay, bottom panel) at 24 h p.i. (Amici et al., 2001).