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  • The EMBO Journal (2002) 21, 5130 - 5140
  • doi:10.1038/sj.emboj.7594736

Baculovirus apoptotic suppressor P49 is a substrate inhibitor of initiator caspases resistant to P35 in vivo

Stephen J. Zoog2, Jennifer J. Schiller3, Justin A. Wetter1, Nor Chejanovsky4 and Paul D. Friesen5

  1. Institute for Molecular Virology, and Department of Biochemistry, Graduate School and College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, WI 53706 USA
  2. Present address: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA
  3. Present address: Department of Pediatrics, Medical School of Wisconsin, Milwaukee, WI 53226, USA
  4. Entomology Department, Institute of Plant Protection, Agricultural Research Organization, Bet Dagan, Israel 50250
  5. Institute for Molecular Virology, R.M.Bock Laboratories, University of Wisconsin-Madison, 1525 Linden Drive, Madison, WI 53706-1596, USA

Correspondence to:

Paul D. Friesen, E-mail: pfriesen@wisc.edu

Received 28 January 2002; Accepted 14 August 2002; Revised 7 August 2002

Caspases play a critical role in the execution of metazoan apoptosis and are thus attractive therapeutic targets for apoptosis-associated diseases. Here we report that baculovirus P49, a homolog of pancaspase inhibitor P35, prevents apoptosis in invertebrates by inhibiting an initiator caspase that is P35 insensitive. Consequently P49 blocked proteolytic activation of effector caspases at a unique step upstream from that affected by P35 but downstream from inhibitor of apoptosis Op-IAP. Like P35, P49 was cleaved by and stably associated with its caspase target. Ectopically expressed P49 blocked apoptosis in cultured cells from a phylogenetically distinct organism, Drosophila melanogaster. Furthermore, P49 inhibited human caspase-9, demonstrating its capacity to affect a vertebrate initiator caspase. Thus, P49 is a substrate inhibitor with a novel in vivo specificity for a P35-insensitive initiator caspase that functions at an evolutionarily conserved step in the caspase cascade. These data indicate that activated initiator caspases provide another effective target for apoptotic intervention by substrate inhibitors.

  • Keywords:

    • apoptosis,
    • baculovirus P49,
    • caspase inhibitor P35,
    • Drosophila melanogaster,
    • IAP