Inhibitor of apoptosis (iap) genes have been identified in the genomes of two independent families of insect viruses, the Baculoviridae and the Entomopoxvirinae. In this report, we examined the functional attributes of the Amsacta moorei entomopoxvirus-encoded IAP protein (AMV-IAP). The binding specificity of the individual baculoviral IAP repeat (BIR) domains of AMV-IAP was investigated by using a random-peptide, phage display library, and sequences similar to the amino termini of proapoptotic Drosophila proteins in the Reaper/Hid/ Grim family were identified. Furthermore, the BIR domains of AMV-IAP protein were demonstrated to bind the mammalian IAP inhibitor Smac through the AVPI tetrapeptide sequence, suggesting that the peptide binding pocket and groove found in the insect and mammalian IAPs is conserved in this viral protein.Interaction analysis implicated BIR1 as the high-affinity site for Grim, while BIR2 interacted more strongly with Hid. Both Grim and Hid were demonstrated to interact with AMV-IAP in vivo, and Grim-or Hid-induced cell death was suppressed when AMV-IAP was coexpressed.Apoptosis, or programmed cell death, is used as a strategic response to eliminate infected cells and thus limit the replication of viruses within the host. The coevolution of viruses and their hosts has resulted in the development of viral strategies to circumvent this response (3). Multiple unrelated virus families have independently targeted the extrinsic death receptor pathways and the intrinsic mitochondrial pathways. Both extrinsic and intrinsic apoptotic pathways trigger a cascade of caspase activation, which leads ultimately to apoptosis. The extrinsic pathways can be thwarted through the expression of virally encoded soluble death receptors, inducing the down-regulation of cellular death receptors or the blockade of the signal transduction pathway by viral FLICE-like inhibitory proteins. Intrinsic pathway signaling can also be blocked at several points, most frequently involving the expression of functional inhibitors of p53 or of viral homologs of the Bcl-2 family (3).Viruses have also developed strategies to target the caspase cascade constituting the ultimate convergence of the extrinsic and intrinsic apoptotic pathways. Several poxvirus-encoded proteins that regulate apoptosis through inhibition of the caspase cascade have been identified (29). Members of the Poxviridae family infect a wide range of vertebrate and invertebrate species, and are subdivided into the Entomopoxvirinae (insect pathogens) and Chordopoxvirinae (mammalian and avian pathogens). Among the Chordopoxvirinae, cowpox virus encodes a unique serpin (serine protease inhibitor) called the cytokine response modifier A (CrmA, also known as SPI-2). CrmA/SPI-2 is able to inhibit a broad range of initiator caspases, including caspase-1, caspase-8, caspase-4, caspase-5, caspase-9, and caspase-10, in order of decreasing affinity, thus inhibiting apoptosis as well as interfering with the host inflammatory reaction (36).The only definitive virally encoded...

Metachromatic leukodystrophy (MLD) is

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