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J. Biol. Chem., Vol. 278, Issue 35, 33175-33184, August 29, 2003

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Leporipoxvirus Cu,Zn-Superoxide Dismutase (SOD) Homologs Are Catalytically Inert Decoy Proteins That Bind Copper Chaperone for SOD^*

Melissa L. T. Teoh, Paula J. Walasek  and David H. Evans 

From the Department of Molecular Biology & Genetics, University of Guelph, Guelph, Ontario N1G 2W1, Canada

Many Chordopoxviruses encode catalytically inactive homologs of cellular Cu-Zn superoxide dismutase (SOD). The biological function of these proteins is unknown, although the proteins encoded by Leporipoxviruses have been shown to promote a slow decline in the level of superoxide dismutase activity in virus-infected cells. To gain more insights into their function, we have further characterized the enzymatic and biochemical properties of a SOD homolog encoded by Shope fibroma virus. Shope fibroma virus SOD has retained the zinc binding properties of its cellular homolog, but cannot bind copper. Site-directed mutagenesis showed that it requires at least four amino acid substitutions to partially restore copper binding activity, but even these changes still did not restore catalytic activity. Reciprocal co-immunoprecipitation experiments showed that recombinant Shope fibroma virus SOD forms very stable complexes with cellular copper chaperones for SOD and these observations were confirmed using glutathione-S-transferase tagged proteins. Similar viral SOD/chaperone complexes were formed in cells infected with a closely related myxoma virus, where we also noted that some of the SOD antigen co-localizes with mitochondrial markers using confocal fluorescence microscopy. About 2% of the viral SOD was subsequently detected in gradient-purified mitochondria extracted from virus-infected cells. These poxviral SOD homologs do not form stable complexes with cellular Cu,Zn-SOD or affect its concentration. We suggest that Leporipoxvirus SOD homologs are catalytically inert decoy proteins that are designed to interfere in the proper metallation and activation of cellular Cu,Zn-SOD. This reaction might be advantageous for tumorigenic poxviruses, since higher levels of superoxide have been proposed to have anti-apoptotic and tumorigenic activity.

Received for publication, January 21, 2003 , and in revised form, May 2, 2003.

^* This work was supported by operating and equipment grants from the Canadian Institutes for Health Research and Natural Sciences and Engineering Research Council (to D. H. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Current address: Dept. of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontarios N2L 3G1, Canada.

To whom correspondence should be addressed: Dept. of Medical Microbiology & Immunology, 1-41 Medical Sciences Building, University of Alberta, Edmonton, Alberta T6G 2H7, Canada. Tel.: 780-492-2308; Fax: 780-492-7521; E-mail: devans{at}ualberta.ca.

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