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Bak and Bax function to limit adenovirus replication through apoptosis induction
Andrea Cuconati1, Kurt Degenhardt, Ramya Sundararajan
1Howard Hughes Medical Institute. Department of Molecular Biology, Rutgers University, Piscataway, New Jersey 08854, USA.
Abstract:
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.
Insights
Adenovirus E1B 19K protein blocks apoptosis by binding Bak, preventing Bax interaction. Bax and Bak proteins mediate an antiviral response, limiting adenovirus replication.
Area of Science:
- Virology
- Cellular Biology
- Immunology
Background:
- Adenovirus infection induces cell proliferation and apoptosis.
- The adenovirus Bcl-2 homologue E1B 19K inhibits apoptosis.
- The precise mechanism of apoptosis induction and its role in productive infection remain unclear.
Purpose of the Study:
- To elucidate the mechanism by which adenovirus induces apoptosis.
- To investigate the role of Bax and Bak proteins in adenovirus-induced apoptosis and viral replication.
- To understand how the adenovirus E1B 19K protein interferes with apoptotic pathways.
Main Methods:
- Utilized wild-type and E1B 19K mutant adenovirus strains.
- Infected wild-type, Bax-deficient, Bak-deficient, and Bax/Bak-double-deficient baby mouse kidney cells.
- Assessed apoptosis induction, Bid cleavage, Bak/Bax conformation changes, Bak-Bax interaction, caspase activation, E1A expression, and viral replication.
Main Results:
- E1B 19K binds Bak, inhibiting Bak-Bax interaction and Bax conformational changes, thereby blocking apoptosis.
- Infection with E1B 19K mutant viruses induced apoptosis via Bak and Bax, independent of Bid cleavage.
- Bax and Bak deficiency led to increased E1A expression and viral replication, indicating apoptosis limits viral spread.
Conclusions:
- Bax and Bak-mediated apoptosis constitutes a critical cellular antiviral response against adenovirus.
- Adenovirus E1B 19K protein actively suppresses this antiviral mechanism to facilitate viral replication.
- Targeting apoptosis pathways is crucial for understanding and potentially controlling adenovirus infections.