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Poxvirus MC160 Protein Utilizes Multiple Mechanisms To Inhibit NF-κB Activation Mediated via Components of the Tumor Necrosis Factor Receptor 1 Signal Transduction Pathway▿

By Daniel Brian Nichols and Joanna L. Shisler

Abstract

Poxviruses express proteins that limit host immune responses to infection. For example, the molluscum contagiosum virus MC160 protein inhibits tumor necrosis factor alpha (TNF-α)-induced NF-κB activation. This event correlates with MC160-induced IKK1 protein degradation, suggesting a mechanism for the above-mentioned phenotype. IKK1 is stabilized when it associates with the cellular heat shock protein 90 (Hsp90). Here, Hsp90 overexpression restored IKK1 levels in MC160-expressing cells, suggesting that MC160 competitively interacted with Hsp90. In support of this, further investigation showed that a mutant MC160 protein comprising only the C-terminal region (C protein) immunoprecipitated with Hsp90. In contrast, Hsp90 IP with a mutant MC160 protein consisting of only the N-terminal tandem death effector domains (DEDs) (N protein) was dramatically decreased. Since cells expressing either the N or C mutant MC160 protein remained similarly resistant to TNF-α-induced NF-κB activation, the N mutant protein probably utilized a different mechanism for inhibiting NF-κB. One likely mechanism for the N protein lies in its association with the DED-containing procaspase-8 protein, a cellular apoptosis precursor protein that regulates NF-κB activation. Here, IPs revealed that this association relied on the presence of the DED-containing N terminus of the MC160 protein but not the C-terminal portion. These interactions appear to have relevance with NF-κB activation, since the expression of the viral DEDs strongly inhibited procaspase-8-mediated NF-κB activation, an event not substantially altered by the C protein. Thus, the MC160 protein utilizes at least two distinct mechanisms for impeding NF-κB activation, association with Hsp90 to result in IKK1 protein degradation or interaction with procaspase-8

Topics: Virus-Cell Interactions
Publisher: American Society for Microbiology (ASM)
OAI identifier: oai:pubmedcentral.nih.gov:2655573
Provided by: PubMed Central
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