Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes

DYSREGULATION of apoptosis can result in inappropriate suppression of cell death, as occurs in the development of some cancers 1 , or in failure to control the extent of cell death, as is believed to occur in acquired immunodeficiency and certain neurodegenera-tive disorders, such as spinal muscular atrophy (SMA). Recently, we isolated a candidate gene, encoding neuronal apoptosis inhibitor protein (NAIP) 2 , for SMA. This gene is homologous to two baculovirus inhibitor of apoptosis proteins 3,4 (Cp-IAP and Op-IAP) and is partly deleted in individuals with type I SMA. A second SMA candidate gene encoding survival motor neuron (SMN), which is contiguous with the NAIP locus on 5ql3.1, was also reported5. Here we demonstrate a NAIP-mediated inhibition of apoptosis induced by a variety of signals, and have identified three additional human complementary DNAs and a Drosophila melanogaster sequence that are also homologous to the baculovirus lAPs. The four open reading frames (ORFs) possess three baculoviral inhibition of apoptosis protein repeat (BIR) domains and a carboxy-terminal RING zinc-finger. The human iap genes have a distinct but overlapping pattern of expression in fetal and adult tissues. These proteins significantly increase the number of known apoptotic suppressors.