NF-kappaB Activation by Viruses
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NF-kappaB Activation by Viruses
As viruses evolve under the highly selective pressures of the immune system, they acquire the capacity to target critical steps in the host cell life, hijacking vital cellular functions to promote viral pathogenesis. Many virus infections induce a proinflammatory response including expression of cytokines and chemokines. The viral surface GP (Glycoproteins), dsRNA (double-stranded RNA), and intracellular viral proteins all have the capacity to activate signal transduction pathways leading to the expression of cytokines and chemokines. The signaling pathways activated by viral infections include the major proinflammatory pathways, and the transcriptional regulators of the NF-KappaB (Nuclear Factor-kappa B)/I-KappaB (Inhibitor of Kappa Light Chain Gene Enhancer in B-Cells) family, which in turn promote the expression of well over 100 proteins participating in the host immune response (Ref.1). The target proteins include a multitude of cytokine and chemokine receptors required for immune recognition, proteins involved in antigen presentation, and adhesion receptors involved in transmigration across blood vessels walls. In addition, some viruses use the NF-KappaB pathway either for its antiapoptotic properties to evade the host defense mechanisms or to trigger apoptosis as a mechanism of virus spread. Many viral products bypass signal-induced stimulation and/or receptor-proximal steps to directly interface with the IKK (I-KappaB Kinases) complex. Because of this extensive role in immune action, NF-KappaB has been termed the central mediator of the immune response.

Multiple families of viruses, including HIV1 (Human Immunodeficiency Virus-1), HTLV1 (Human T-Cell Leukemia Virus-1), HBV (Hepatitis B Virus), HCV (Hepatitis C Virus), EBV (Epstein-Barr Virus) and Influenza virus activate NF-KappaB. This activation may serve several functions: to promote viral replication, prevent virus-induced apoptosis, and mediate the immune response to the invading pathogen. Viral products that activate NF-KappaB include the HTLV1 Tax protein, the HIV1 Tat protein, and the EBV LMP1 (Latent Membrane Protein-1), among others, which act through several distinct mechanisms to enhance virus replication (Ref.2). NF-KappaB is also activated by dsRNA, suggesting that viruses that generate dsRNA replicative intermediates employ a common mechanism to enhance viral replication. Influenza virus HA (Hemagglutinin), MA (Matrix protein), and NP (Nucleoprotein), as well as HBV HBx (X protein of Hepatitis-B) protein and HCV core protein, can also induce NF-KappaB, which is normally found in the cytoplasm complexed with an inhibitory protein, I-KappaB or its various isoforms. Upon infection, signaling events are initiated leading to activation of MEKK1 (MAPK/ERK kinase kinase-1), which promote the activation of other kinases capable of phosphorylating I-KappaB. The kinases responsible for I-KappaB phosphorylation are IKK-Alpha and IKK-Beta. Phosphorylated I-KappaB is subsequently targeted for degradation through the ubiquitin-dependent proteasome pathway. Degradation of I-KappaB unmasks the nuclear localization signal of NF-KappaB, which then migrates to the nucleus and activates transcription along with RNA Pol II (RNA Polymerase) and TBP (TATA Binding Protein).

NF-KappaB is constitutively activated in primary monocytes and myeloid cell lines chronically infected with HIV1. HIV is a retrovirus that infects CD4 T-lymphocytes and monocytes/macrophages through recognition of the CD4 receptor and the coreceptors CXCR4 (Chemokine (C-X-C motif) Receptor-4) and CCR5 (CC-motif Receptor-5) (Ref.3). Binding of GP120 to CD4 results in activation of the tyrosine kinase Lck and the serine/threonine kinase Raf1. This receptor engagement also induces activation of the MAPK (Mitogen Activated Protein kinases) ERK1/2 (Extracellular Signal-Regulated Kinase), and JNK (c-Jun N-terminal Kinase), as well as the GP120 and NF-KappaB. Ras, an upstream signaling molecule of Raf, is also activated by CD4 cross-linking and can activate NF-KappaB. Binding of HIV1 to CD4 also activates PI3K (Phosphatidylinositol 3-Kinase), which functions upstream of Akt1 to stimulate IKK. Therefore, CD4 signaling upon HIV1 binding or GP120 ligation may activate NF-KappaB via two different but closely related pathways, one through Lck and Raf, and a second through PI3K, Akt1, and IKK. Active NF-KappaB then translocates to the nucleus, where it mediates the activation of viral and cellular gene transcription by binding to its specific recognition sequences in the enhancer region (Ref.4). HIV regulatory or accessory proteins Tat protein and Vpr (Viral protein R) may also stimulate NF-KappaB activity. Activation of NF-KappaB by Tat protein proceeds via IKK, which is constitutively active in HIV-infected cells. Moreover, the ability of Tat protein to activate NF-KappaB also requires PKR (RNA-dependent Protein Kinase-R) or PKC (Protein Kinase-C). Vpr, which is required for optimal replication of HIV in vivo, is produced late in the HIV life cycle and assembled into the virion (Ref.5). Vpr enhances the trans-activating function of NF-KappaB.

The mechanism of NF-KappaB activation by EBV involves the interaction of GP350 with its cognate cellular receptor CD21 that induces intracellular signaling from CD21 resulting in rapid activation of NF-KappaB as well as activation of PKC and PI3K. At later stages of infection, LMP1 is produced and inserted in the cellular membrane. LMP1 activates NF-KappaB by usurping the cytoplasmic TNF (Tumor Necrosis Factor) signaling pathway. Consequently, like the TNF-Alpha receptor, LMP1 activates NF-KappaB through a mechanism common to many stimuli (Ref.6), where signals from TRAF2 (TNFR-Associated Factor-2) and RIP (Receptor Interacting Kinase) converge at NIK (NF-KappaB-Inducing Kinase) followed by activation of IKK and subsequent nuclear translocation of NF-KappaB. EBNA2 (EBV Nuclear Antigen-2) represents yet another EBV-encoded protein with the capacity to modulate cellular signaling.

The expression of a single viral protein like the HTLV1 Tax, and HBx of HBV or the E3/19K protein of Adenovirus is sufficient to activate NF-KappaB. E3/19K resides in the ER (Endoplasmic Reticulum) and potently activates NF-KappaB (Ref.7). The inducing signal is triggered by the accumulation of proteins in the ER membrane, a condition termed "ER overload" that causes Ca2+ release from the ER. Because NF-KappaB plays a key role in mounting an immune response, ER overload caused by viral proteins constitute a simple antiviral response with broad specificity. HBx modulates host cellular gene transcription by activating NF-KappaB through the Ras and PKC pathways. HBx induce I-KappaB-Alpha degradation and target it for proteolytic processing through the MAPK pathway and MEKK1 activation. These events increase nuclear transport of RelA (p65) and c-Rel-related complexes and transactivation of NF-KappaB-responsive genes. In addition to HBx, the protein resulting from the large translational product of the surface antigen HBsAg gene (LHB) also activates GP120 and NF-KappaB and downstream activation of the kinase Raf1 is a prerequisite for LHB-dependent activation. MV (Measles Virus) and HCV core C protein inhibit NF-KappaB activation at either the IKK activation step by E1A of Adenovirus or at the I-KappaB-Alpha degradation step.

CMV (Cytomegalovirus) stimulates a large number of typical proinflammatory signaling events, including nuclear translocation of NF-KappaB. One of the major components of the CMV virion is the Glycoprotein GB, and a significant proportion of the virus-host interactions are mediated through GB (Ref.8). The early cellular response to human CMV infection is production of IP3 (Inositol 1,4,5-triphosphate) and DAG (Diacylglycerol). The subsequent calcium flow and PKC activation is involved in early activation of transcription factors interacting with DNA motifs, including NF-KappaB. The mechanism of activation of NF-KappaB by CMV involves the liberation of the transcription factor from the inhibitory subunit I-KappaB-Alpha but not I-KappaB-Beta (Ref.9). The early activation of NF-KappaB is amplified by other mechanisms later during infection.

The HSV (Herpes Simplex Virus) genome encodes at least 11 GPs, which alone or in concert play different roles in viral adsorption, entry, cell-to-cell spread, immune evasion etc. Glycoprotein D (GD) is central to viral entry, which is dependent on the interaction of GD with a cellular entry mediator. At present, three entry mediators have been identified, termed HveA, HveB, and HveC, and of these at least the TNF receptor family member HveA is known to be a signaling receptor. HSV infection triggers at least two cellular signaling pathways: one UV insensitive and dependent on GD, and the other is UV sensitive and dependent on a functional viral genome. HSV uses HveA as receptor and HveA signaling leads to activation of NF-KappaB and Activator Protein-1 (Ref.10). At later stages of infection (i.e., 3 to 4 h post infection), UV-sensitive signaling is initiated, leading to a strong activation of NF-KappaB and Activator Protein-1. The mechanism of sustained NF-KappaB activation by HSV is dependent on viral entry and immediate-early gene expression.

The cellular signaling induced by Influenza virus infection results in activation of the MAP kinases p38 and JNK and the downstream transcription factors NF-KappaB and Activating Protein-1. The mechanism of NF-KappaB activation include overload of HA in the ER, a process that activates NF-KappaB through the release of calcium. Two other influenza virus proteins, MA and NP also promote NF-KappaB activation, although this occurs through an ER-independent mechanism. In addition to viral proteins, the infected cell as an alert signal senses influenza virus dsRNA. The dsRNA initiates signaling events through a mechanism dependent on the dsRNA-activated PKR. This PKR-dependent virus-induced cellular stress response is an important part of the first line of defense against virus infections (Ref.11). The influenza virus has, however, developed mechanisms to mask the potent PKR-activating ability of its RNA.

NF-KappaB is involved in the gene expression of Retroviruses (HIV), Adenoviruses, Papova viruses and Herpes viruses (Ref.2). A low level of NF-KappaB activation permits some viruses to maintain their chronic infections, whereas in other cases, viral proteins inhibit NF-KappaB activity and either enhance replication or contribute to viral pathogenicity. Certain pathogenic viruses, including Human Herpes virus-8 and the Kaposi’s sarcoma Herpes virus encode proteins with such DEDs (Death Effector Domains), which block cell death induced by DED-containing receptors. These proteins (called FLICE inhibitory proteins or vFLIPs) also physically interact with several proteins in the NF-KappaB pathway, such as the TRAFs, RIP, NIK, and the IKKs, suggesting that this pathway affects the natural history of infection by Herpes viruses as well.