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

Abstract

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 speci®city 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.

Phosphorylation Drives an Apoptotic Protein to Activate Antiapoptotic Genes

“…However, viruses either encode certain proteins or modulate cellular proteins to evade transcription repression and apoptosis (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). PML nuclear bodies and their associated proteins such as PML, Sp100 (ND10-associated speckled, 100 kDa), Daxx, and ATRX (␣ thalassemia/mental retardation syndrome X-linked) as cellular defenses against viruses have been studied extensively (42)(43)(44)(45)(46)(47)(48)(49)(50).…”

“…In contrast, during early infection, viruses protect cells from dying for their own benefit. For this, they generally initiate cell survival pathways by recruiting their encoded proteins (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Because viruses control many cellular processes utilizing a limited number of viral proteins, the function of the viral protein may depend on its localization in the cell during various stages of viral infection.…”

Induction of reaper ortholog mx in mosquito midgut cells following baculovirus infection

“…29 Several antiapoptotic genes have been characterized in lepidopteran baculoviruses, including iap, p35, and p49. 4,30 While injecting wild-type virus to moth larvae usually leads to necrosis, injecting viruses with mutated p35 induced massive apoptosis. 31 Consequently, the infectivity of the mutant virus was much lower than that of the wild-type virus.…”

Viral Subversion of Apoptotic Enzymes: Escape from Death Row

“…p35 is least effective against caspase-2 and caspase-9. The related p49 protein from Spodoptera littoralis Nucleopolyhedrovirus (SlNPV) (34) inhibits a wider range of caspases compared with p35, including caspase-2 and caspase-9 as well as Drosophila Nedd2-like caspase (DRONC), a caspase-9-like initiator caspase (56,142) (Table 1). However, unlike p35, p49 cannot suppress DrICE activity, suggesting host-specific roles for this class of inhibitors (70).…”