NF-κB as a target for oncogenic viruses

Abstract

NF-κB is a pivotal transcription factor that controls cell survival and proliferation in diverse physiological processes. The activity of NF-κB is tightly controlled through its cytoplasmic sequestration by specific inhibitors, IκBs. Various cellular stimuli induce the activation of an IκB kinase, which phosphorylates IκBs and triggers their proteasomal degradation, causing nuclear translocation of activated NF-κB. Under normal conditions, the activation of NF-κB occurs transiently, thus ensuring rapid but temporary induction of target genes. Deregulated NF-κB activation contributes to the development of various diseases, including cancers and immunological disorders. Accumulated studies demonstrate that the NF-κB signaling pathway is a target of several human oncogenic viruses, including the human T cell leukemia virus type 1, the Kaposi sarcoma-associated herpesvirus, and the Epstein-Bar virus. These viruses encode specific oncoproteins that target different signaling components of the NF-κB pathway, leading to persistent activation of NF-κB. This chapter will discuss the molecular mechanisms by which NF-κB is activated by the viral oncoproteins.

Fig. 1

Canonical NF-κB activation by TCR/CD28 and HTLV1 Tax. Canonical NF-κB activation by the T-cell receptor (TCR) and CD28 costimulatory molecule involves transient assembly of an intermediate signaling complex composed of Carma1, Bcl10, and Malt1. This so-called CBM complex is also associated with the ubiquitin-conjugating enzyme (E2) Ubc13/Uev1 and a yet-to-be characterized E3 ubiquitin ligase. Within this signaling complex, Bcl10 and probably also Malt1 are conjugated with K63-linked ubiquitin chains that function as a platform to recruit the IKK and Tak1 complexes for their activation. Tax forms a stable complex with IKK and Tak1 and thereby persistently activates these kinases and NF-κB. This viral pathway involves K63 type of ubiquitination of Tax, although how ubiquitination regulates the Tax-specific NF-κB signaling is less clear. Ubiquitination, and possibly Pin1-mediated isomerization, of Tax may facilitate the binding of Tax to NEMO. It is also possible that Tax ubiquitination facilitates its binding by the Tak1 complex via the ubiquitin-association function of Tab2.

Fig. 2

Tax-specific noncanonical NF-κB pathway. Noncanonical NF-κB signaling pathway is stimulated in B cells by the BAFFR and CD40 signals. This pathway is negatively regulated by TRAF3, which recruits the E3 ubiquitin ligase c-IAP1 or c-IAP2 via TRAF2 and induces ubiquitin-dependent degradation of NIK. The receptor signals induce degradation of TRAF3 and TRAF2, leading to accumulation of NIK and NIK/IKKα-mediated p100 C-termimal phosphorylation. The phosphorylated p100 is then processed through the ubiquitin/proteasome pathway and produce the mature NF-κB2 p52 as a dimer with RelB. Under normal conditions, active processing of p100 does not occur in T cells. However, in HTLV1 infected T cells, Tax initiates an active noncanonical NF-κB pathway by bridging p100 and IKKα. In contrast to the cellular pathway, which is independent of NEMO, the viral pathway requires NEMO, which may function as an adaptor for Tax/IKKα association.

Fig 3

Model for the NF-κB activity kinetics throughout the course KSHV or EBV infection. Viral entry can trigger NF-κB activation, which can be caused by receptor binding and activity of the tegument protein encoded in ORF75 or KSHV. NF-κB induces expression of latent genes, such as EBV LMP1 and KSHV vFLIP, that in turn contribute to constitutive activation of the NF-κB pathway in the latently infected cells. Viral latency persists for a variable period of time, until unknown triggers downregulate NF-κB signaling and/or perturb the latent/lytic phase homeostasis. Consequently, a proportional increment in the expression of the EBV ZTA, EBV RTA and KSHV RTA major viral lytic activators occurs, which in turn further downregulates NF-κB, thereby propagating the lytic cascade. Once a biological threshold is reached, the latent-lytic switch is completed and viral replication occurs. Later in the lytic cascade, the expression of some viral lytic genes, such as KSHV vGPCR, may contribute to a new wave of NF-κB activation, which may have a role in extending the cell lifespan sufficiently to allow release of new viral particles until cytopathic effects of viral infection cause cell death.

Fig 4

NF-κB activation by KSHV vFLIP. The vFLIP protein encoded by KSHV can induce both the canonical (right) and noncanonical (left) NF-κB pathways. Direct binding of vFLIP to NEMO results in activation of IKKα and IKKβ, which in turn lead to cleavage of p100 and phosphorylation of IκB to induce nuclear translocation of RelB/p52 and Rel (p65)/p50 complexes, respectively.

Fig 5

Patterns of EBV latent gene expression in healthy individuals and in malignant lymphomas. The patterns of EBV gene expression infection described in different B cell subsets are shown in the upper table. Corresponding expression profiles in malignant lymphomas have been designated Latencies I, II, and III, and are shown in the lower table. EBER in situ hybridization is used to detect the presence of EBV, immunohistochemical positivity for LMP1 denotes latency II or III, and EBNA 2 protein expression together with LMP1 is indicative of latency III. Those lymphomas expressing LMP1 have constitutive NF-κB activity, while in other lymphomas this activity may be present but more variable and sometimes induced by exogenous signals, such as that induced by CD40, BAFF and APRIL or by cellular genetic alterations, such as inactivating mutations of A20 or CARD11. Primary effusion lymphomas, while not expressing LMP1, also contain KSHV which induces NF-κB through expression of vFLIP.