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

Helen Everett, Michele Barry, Siow Fong Lee, Xuejun Sun, Kathryn Graham, James Stone, R. Chris Bleackley, Grant McFadden

Research output: Contribution to journalArticle

115 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1487-1498
Number of pages12
JournalJournal of Experimental Medicine
Volume191
Issue number9
DOIs
StatePublished - May 1 2000
Externally publishedYes

Keywords

  • Apoptosis
  • Inflammation
  • Mitochondria
  • Monocyte
  • Poxviridae infection

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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