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Journal of Virology, April 2009, p. 3162-3174, Vol. 83, No. 7
0022-538X/09/$08.00+0     doi:10.1128/JVI.02009-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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

Daniel Brian Nichols and Joanna L. Shisler*

Department of Microbiology, College of Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801

Received 23 September 2008/ Accepted 13 January 2009

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.

* Corresponding author. Mailing address: B103 Chemical and Life Sciences Building, 601 S. Goodwin Avenue, Urbana, IL 61801. Phone: (217) 265-6450. Fax: (217) 244-6697. E-mail: jshisler{at}illinois.edu

{triangledown} Published ahead of print on 21 January 2009.

Journal of Virology, April 2009, p. 3162-3174, Vol. 83, No. 7
0022-538X/09/$08.00+0     doi:10.1128/JVI.02009-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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