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Journal of Virology, March 2009, p. 2469-2479, Vol. 83, No. 6
0022-538X/09/$08.00+0     doi:10.1128/JVI.01986-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Inhibition of the Ubiquitin-Proteasome System Prevents Vaccinia Virus DNA Replication and Expression of Intermediate and Late Genes{triangledown}

P. S. Satheshkumar, Luis C. Anton,{dagger} Patrick Sanz,{ddagger} and Bernard Moss*

Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-3210

Received 19 September 2008/ Accepted 24 December 2008

The ubiquitin-proteasome system has a central role in the degradation of intracellular proteins and regulates a variety of functions. Viruses belonging to several different families utilize or modulate the system for their advantage. Here we showed that the proteasome inhibitors MG132 and epoxomicin blocked a postentry step in vaccinia virus (VACV) replication. When proteasome inhibitors were added after virus attachment, early gene expression was prolonged and the expression of intermediate and late genes was almost undetectable. By varying the time of the removal and addition of MG132, the adverse effect of the proteasome inhibitors was narrowly focused on events occurring 2 to 4 h after infection, the time of the onset of viral DNA synthesis. Further analyses confirmed that genome replication was inhibited by both MG132 and epoxomicin, which would account for the effect on intermediate and late gene expression. The virus-induced replication of a transfected plasmid was also inhibited, indicating that the block was not at the step of viral DNA uncoating. UBEI-41, an inhibitor of the ubiquitin-activating enzyme E1, also prevented late gene expression, supporting the role of the ubiquitin-proteasome system in VACV replication. Neither the overexpression of ubiquitin nor the addition of an autophagy inhibitor was able to counter the inhibitory effects of MG132. Further studies of the role of the ubiquitin-proteasome system for VACV replication may provide new insights into virus-host interactions and suggest potential antipoxviral drugs.

* Corresponding author. Mailing address: Laboratory of Viral Diseases, NIAID, NIH, 33 North Drive, MSC 3210, Bethesda, MD 20892-3210. Phone: (301) 496-9869. Fax: (301) 480-1535. E-mail: bmoss{at}nih.gov

{triangledown} Published ahead of print on 7 January 2009.

{dagger} Present address: Centro de Biologia Molecular Severo Ochoa, CSIC/UAM, Madrid, Spain.

{ddagger} Present address: Uniformed Services University of the Health Sciences, Bethesda, MD 20814.

Journal of Virology, March 2009, p. 2469-2479, Vol. 83, No. 6
0022-538X/09/$08.00+0     doi:10.1128/JVI.01986-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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