Bak and Bax function to limit adenovirus replication through apoptosis induction.
Adenovirus infection and expression of E1A induces both proliferation and apoptosis, the latter of which is blocked by the adenovirus Bcl-2 homologue E1B 19K. The mechanism of apoptosis induction and the role that it plays in productive infection are not known. Unlike apoptosis mediated by death receptors, infection with proapoptotic E1B 19K mutant viruses did not induce cleavage of Bid but nonetheless induced changes in Bak and Bax conformation, Bak-Bax interaction, caspase 9 and 3 activation, and apoptosis. In wild-type-adenovirus-infected cells, in which E1B 19K inhibits apoptosis, E1B 19K was bound to Bak, precluding Bak-Bax interaction and changes in Bax conformation. Infection with E1B 19K mutant viruses induced apoptosis in wild-type and Bax- or Bak-deficient baby mouse kidney cells but not in those deficient for both Bax and Bak. Furthermore, Bax and Bak deficiency dramatically increased E1A expression and virus replication. Thus, Bax- and Bak-mediated apoptosis severely limits adenoviral replication, demonstrating that Bax and Bak function as an antiviral response at the cellular level.
Cuconati
Andrea
A
Howard Hughes Medical Institute. Department of Molecular Biology, Rutgers University, Piscataway, New Jersey 08854, USA.
Degenhardt
Kurt
K
Sundararajan
Ramya
R
Anschel
Alan
A
White
Eileen
E
D017501:Adenovirus E1B Proteins / Q000378:metabolism; D000260:Adenoviruses, Human / Q000472:pathogenicity* / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000166:cytology; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2; D014779:Virus Replication / Q000187:drug effects*; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
D017501:Adenovirus E1B Proteins; C494772:BAK1 protein, human; C494826:BAX protein, human; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D020169:Caspases