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

被引:30
|
作者
Nichols, Daniel Brian [1 ]
Shisler, Joanna L. [1 ]
机构
[1] Univ Illinois, Coll Med, Dept Microbiol, Urbana, IL 61801 USA
基金
美国国家卫生研究院;
关键词
MOLLUSCUM CONTAGIOSUM VIRUS; TOLL-LIKE RECEPTORS; IKK-ALPHA; VACCINIA VIRUS; KINASE-ALPHA; DERMATOTROPIC POXVIRUS; COMPLEX-FORMATION; GENE-EXPRESSION; MICE LACKING; P65; SUBUNIT;
D O I
10.1128/JVI.02009-08
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Poxviruses express proteins that limit host immune responses to infection. For example, the molluscum contagiosum virus MC160 protein inhibits tumor necrosis factor alpha (TNF-alpha)-induced NF-kappa B 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-alpha-induced NF-kappa B activation, the N mutant protein probably utilized a different mechanism for inhibiting NF-kappa B. 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-kappa B 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-kappa B activation, since the expression of the viral DEDs strongly inhibited procaspase-8-mediated NF-kappa B activation, an event not substantially altered by the C protein. Thus, the MC160 protein utilizes at least two distinct mechanisms for impeding NF-kappa B activation, association with Hsp90 to result in IKK1 protein degradation or interaction with procaspase-8.
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页码:3162 / 3174
页数:13
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