M11L: A novel mitochondria-localized protein of myxoma virus that blocks apoptosis of infected leukocytes

M11L, a novel 166-amino acid membrane-associated protein expressed by the p oxvirus, myxoma virus, was previously found to modulate apoptosis after inf ection of rabbit leukocytes. Furthermore, infection of rabbits with an M11L knockout virus unexpectedly produced lesions with a profound proinflammato ry phenotype. We show here that M11L is antiapoptotic when expressed indepe ndently of other viral proteins, and is directed specifically to mitochondr ia by a short COOH-terminal region that is necessary and sufficient for tar geting. This targeting region consists of a hydrophobic domain flanked by b asic amino acid residues, adjacent to a positively charged tail. M11L block s staurosporine-induced apoptosis by preventing mitochondria from undergoin g a permeability transition, and the mitochondrial localization of this pro tein is essential for this function. We show that M11L is specifically requ ired to inhibit the apoptotic response of monocytes/macrophages during viru s 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 a nd proinflammatory phenotypes of the M11L knockout virus. We suggest that a poptosis of tissue macrophages represents an important antiviral defense, a nd that the inhibition of apoptosis by viral proteins can be directed in a cell-specific fashion.