title: MCMV-mediated inhibition of the pro-apoptotic Bak protein is required for optimal in vivo replication.
abstract: Successful replication and transmission of large DNA viruses such as the cytomegaloviruses (CMV) family of viruses depends on the ability to interfere with multiple aspects of the host immune response. Apoptosis functions as a host innate defence mechanism against viral infection, and the capacity to interfere with this process is essential for the replication of many viruses. The Bcl-2 family of proteins are the principle regulators of apoptosis, with two pro-apoptotic members, Bax and Bak, essential for apoptosis to proceed. The m38.5 protein encoded by murine CMV (MCMV) has been identified as Bax-specific inhibitor of apoptosis. Recently, m41.1, a protein product encoded by the m41 open reading frame (ORF) of MCMV, has been shown to inhibit Bak activity in vitro. Here we show that m41.1 is critical for optimal MCMV replication in vivo. Growth of a m41.1 mutant was attenuated in multiple organs, a defect that was not apparent in Bak(-/-) mice. Thus, m41.1 promotes MCMV replication by inhibiting Bak-dependent apoptosis during in vivo infection. The results show that Bax and Bak mediate non-redundant functions during MCMV infection and that the virus produces distinct inhibitors for each protein to counter the activity of these proteins.
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Nedlands, Western Australia, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Fleming
authors.forename: Marc
authors.initials: M
authors.lastname: Kvansakul
authors.forename: Valentina
authors.initials: V
authors.lastname: Voigt
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Kile
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Kluck
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.forename: Mariapia A
authors.initials: MA
authors.lastname: Degli-Esposti
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Andoniou
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D007113:Immunity, Innate; D051034:Inhibitor of Apoptosis Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018146:Muromegalovirus / Q000378:metabolism / Q000472:pathogenicity*; D014779:Virus Replication / Q000502:physiology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein