Reovirus Infection or Ectopic Expression of Outer Capsid Protein mu 1 Induces Apoptosis Independently of the Cellular Proapoptotic Proteins Bax and Bak

• Published in: Journal of virology Vol. 85; no. 1; pp. 296 - 304
• Main Authors: Wisniewski, Meagan L, Werner, Brenda G, Hom, Louis G, Anguish, Lynne J, Coffey, Caroline M, Parker, John SL
• Format: Journal Article
• Language: English
• Published: 01-01-2011
• Subjects: Reovirus
• ISSN: 0022-538X; 1098-5514
• DOI: 10.1128/JVI.01982-10

Mammalian orthoreoviruses induce apoptosis in vivo and in vitro; however, the specific mechanism by which apoptosis is induced is not fully understood. Recent studies have indicated that the reovirus outer capsid protein mu 1 is the primary determinant of reovirus-induced apoptosis. Ectopically expressed mu 1 induces apoptosis and localizes to intracellular membranes. Here we report that ectopic expression of mu 1 activated both the extrinsic and intrinsic apoptotic pathways with activation of initiator caspases-8 and -9 and downstream effector caspase-3. Activation of both pathways was required for mu 1-induced apoptosis, as specific inhibition of either caspase-8 or caspase-9 abolished downstream effector caspase-3 activation. Similar to reovirus infection, ectopic expression of mu 1 caused release into the cytosol of cytochrome c and smac/DIABLO from the mitochondrial intermembrane space. Pancaspase inhibitors did not prevent cytochrome c release from cells expressing mu 1, indicating that caspases were not required. Additionally, mu 1- or reovirus-induced release of cytochrome c occurred efficiently in Bax-/-Bak-/- mouse embryonic fibroblasts (MEFs). Finally, we found that reovirus-induced apoptosis occurred in Bax-/-Bak-/- MEFs, indicating that reovirus-induced apoptosis occurs independently of the proapoptotic Bcl-2 family members Bax and Bak.