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Review
. 2014 Oct;72(1):32-44.
doi: 10.1111/2049-632X.12210. Epub 2014 Aug 28.

The role of the IKK complex in viral infections

Moushimi Amaya  1 , Forrest Keck, Charles Bailey, Aarthi Narayanan
Affiliations
Review

The role of the IKK complex in viral infections

Moushimi Amaya et al. Pathog Dis. 2014 Oct.

Abstract

The NF-κB signal transduction pathway is a critical regulator of multiple cellular functions that ultimately shift the balance between cell survival and death. The cascade is activated by many intrinsic and extrinsic stimuli, which is transduced via adaptor proteins to phosphorylate the IκB kinase (IKK) complex, which in turn phosphorylates the inhibitory IκBα protein to undergo proteasomal degradation and sets in motion nuclear events in response to the initial stimulus. Viruses are important modulators of the NF-κB cascade and have evolved multiple mechanisms to activate or inhibit this pathway in a manner conducive to viral multiplication and establishment of a productive infectious cycle. This is a subject of extensive research by multiple laboratories whereby unraveling the interactions between specific viral components and members of the NF-κB signal transduction cascade can shed unique perspectives on infection associated pathogenesis and novel therapeutic targets. In this review, we highlight the interactions between components of the IKK complex and multiple RNA and DNA viruses with the emphasis on mechanisms by which the interaction feeds the infection. Understanding these interactions will shed light on the exploitative capabilities of viruses to maintain an environment favorable for a productive infection.

Keywords: IKK complex; host response; viral proteins.

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Figures

Figure 1
Figure 1
The canonical and noncanonical NF‐κB pathways. The canonical pathway is stimulated by a variety of signals that are detected by cell surface receptors such as TLRs, TNFRs, and antigen receptors. The signal is transduced to the adaptor protein TRAF such that TBK‐1 phosphorylates IKKβ and IKKα. IKK‐mediated IκBα phosphorylation is followed by proteasomal degradation resulting in nuclear translocation of the NF‐κB heterodimer p65/p50 to activate or repress target gene expression. The noncanonical NF‐κB pathway is triggered by stimuli such as lipopolysaccharide. In this pathway, NIK phosphorylates the homodimer IKKα which mediates the phosphorylation and ubiquitylation of p100/RelB. Consequently, p100 is processed to the smaller isoform p52 and the p52/RelB heterodimer translocates to the nucleus to activate or repress target gene expression.
Figure 2
Figure 2
HCV infection inhibits the TNF‐α induced NF‐κB activation. In HCV infections, the nonstructural proteins NS5A and NS5B have been implicated in activating the NF‐κB pathway. The mechanism by which NS5A and NS5B inhibit NF‐κB has not yet been determined and as such we have denoted a probable mechanism by dashed lines. However, HCV utilizes IKKα independent of the NF‐κB pathway at later stages of infection. HCV core protein associates with lipid droplets during viral assembly.
Figure 3
Figure 3
VEEV nsP3 interaction with IKKβ to activate the NF‐κB cascade. VEEV polyprotein processing results in nsP3 interacting with the IKKβ subunit of the IKK complex. It has yet to be determined whether this interaction is required for activation of the NF‐κB cascade and hence is denoted by dashed lines. The nsP3‐IKKβ interaction is required for VEEV replication in infected cells.
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