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 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.
Everett
H
H
Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Barry
M
M
Lee
S F
SF
Sun
X
X
Graham
K
K
Stone
J
J
Bleackley
R C
RC
McFadden
G
G
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002451:Cell Compartmentation; D019070:Cell Lineage; D049452:Green Fluorescent Proteins; D007962:Leukocytes / Q000821:virology*; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics / Q000302:isolation & purification; D008264:Macrophages / Q000821:virology; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D008969:Molecular Sequence Data; D009000:Monocytes / Q000821:virology; D009233:Myxoma virus / Q000378:metabolism*; D010539:Permeability; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000302:isolation & purification; D014764:Viral Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000302:isolation & purification
D008164:Luminescent Proteins; D011993:Recombinant Fusion Proteins; D014764:Viral Proteins; D049452:Green Fluorescent Proteins; C077309:M11L protein, Myxoma virus