The Journal of Experimental Medicine
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Published online 24 April 2000.
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© The Rockefeller University Press, 0022-1007/2000/5/1487/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 9, May 1, 2000 1487-1498

Original Article

M11L: A Novel Mitochondria-localized Protein of Myxoma Virus That Blocks Apoptosis of Infected Leukocytes

Helen Everetta, Michele Barrya, Siow Fong Leeb, Xuejun Sunc, Kathryn Grahamc, James Stonea, R. Chris Bleackleya, and Grant McFaddend
a Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada
b Department of Laboratory Medicine and Pathology, University of Alberta Hospital, Edmonton, Alberta T6G 2B7, Canada
c Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Alberta T6G 1Z2, Canada
d Department of Microbiology and Immunology, University of Western Ontario, and John P. Robarts Research Institute, London, Ontario N6G 2V4, Canada

Correspondence to: Grant McFadden, Department of Microbiology and Immunology, University of Western Ontario, and John P. Robarts Research Institute, London, Ontario N6G 2V4, Canada. Tel:519-663-3184 Fax:519-663-3847 E-mail:mcfadden{at}rri.on.ca.

M11L, a novel 166–amino acid membrane-associated protein expressed by the poxvirus, myxoma virus, was previously found to modulate apoptosis after infection of rabbit leukocytes. Furthermore, infection of rabbits with an M11L knockout virus unexpectedly produced lesions with a profound proinflammatory phenotype. We show here that M11L is antiapoptotic when expressed independently of other viral proteins, and is directed specifically to mitochondria by a short COOH-terminal region that is necessary and sufficient for targeting. This targeting region consists of a hydrophobic domain flanked by basic amino acid residues, adjacent to a positively charged tail. M11L blocks staurosporine-induced apoptosis by preventing mitochondria from undergoing a permeability transition, and the mitochondrial localization of this protein is essential for this function. We show that M11L is specifically required to inhibit the apoptotic response of monocytes/macrophages during virus infection, as cells of this lineage undergo apoptosis when infected with the M11L knockout virus. As monocyte apoptosis is uniquely proinflammatory, we propose that this observation reconciles the paradoxical proapoptotic and proinflammatory phenotypes of the M11L knockout virus. We suggest that apoptosis of tissue macrophages represents an important antiviral defense, and that the inhibition of apoptosis by viral proteins can be directed in a cell-specific fashion.

Key Words: apoptosis, inflammation, mitochondria, monocyte, Poxviridae infection


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