IAP family proteins - Suppressors of apoptosis

Abstract

IAP family proteins are conserved throughout animal evolution and can block apoptosis when expressed in cells derived from multiple species. In many instances IAP family proteins can suppress apoptosis across species barriers (for review, see Clem and Duckett 1998), implying that although the details of their regulation may vary, these proteins evidently target a common mechanism involved in programmed cell death. Although all IAP family proteins require at least one BIR domain for their anti-apoptotic function, it should be emphasized that not all BIR-containing proteins are necessarily involved in apoptosis regulation as indicated by the failure of the Ac-IAP protein to suppress apoptosis despite harboring a BIR domain. Until proven otherwise, the most likely explanation for how IAPs prevent apoptosis is by binding to and inhibiting caspases, as indicated by recent studies (Deveraux et al. 1997 1998; Roy et al. 1997; Takahashi et al. 1998; Tamm et al. 1998). Assuming that this biased viewpoint is correct, how important are IAP family proteins likely to be for ensuring cell survival in vivo? The answer to that question probably depends on the type of cell under investigation and the specific cell death stimulus involved. I IAPs function primarily as inhibitors of caspases, then we can anticipate from other experiments where artificial means were used to suppress these proteases that APs will be capable of rescuing cells from some cell death signals but not others (Green and Reed 1998). Mitochondrial involvement appears to be one of the key variables that determines whether caspase inhibitors are sufficient to provide long-term protection and preservation of clonigenic potential, versus merely delaying death by converting an apoptotic stimulus into a necrotic one (Reed 1997; Green and Reed 1998). In many types of cells, loss of cytochrome c from mitochondria, for example, has two ways of killing cells: (1) activation of caspases through Apaf-1; or (2) cessation of mitochondrial electron chain transport with subsequent ATP depletion, generation of reactive oxygen species, and related sequelae. If the role of IAPs is relegated to caspase suppression, this may prevent cytochrome c-induced apoptosis, but not necessarily stop cell death induced by caspase-independent mechanisms. Recent studies in which release of cytochrome c was found to be a potentially reversible event suggest that whether cytochrome c loss from mitochondria defines a cell death commitment point will likely vary among cell types and depending on a variety environmental factors (Q. Chen et al. 1998). These factors may include the extent to which cells are able to produce sufficient ATP from anaerobic glycolysis in the cytosol and the method by which mitochondrial membrane barrier function was altered to allow for exodus of cytochrome c (i.e., reversible versus irreversible/rupture). Defining the in vivo requirements for IAPs in the maintenance of cell survival may be difficult because of potential redundancy. Humans have at least five and possibly more IAP family genes and even lower organisms, such as Drosophila, appear to contain at least two IAP genes, implying evolutionary pressure to ensure adequate back-up if one of these genes were to become inactivated. If IAPs do indeed function predominantly as caspase inhibitors, then one could imagine a very important role for these endogenous protease inhibitors in ensuring that the small amounts of adventitial caspase activation, which must surely occur on a routine basis, do not amplify out of control, resulting in inappropriate cell death. In this regard, virtually every other protease system studied to date contains molecules whose sole function is directed toward dampening proteolysis through the cascade (for review, see Colman et al. 1994), thus ensuring that biologically appropriate triggering of the pathway only occurs when certain thresholds are surpassed. By analogy, it is attractive to consider IAP family proteins in the same way, as proteins that set thresholds for how much caspase activation is necessary to successfully trigger apoptosis. Through alterations in the levels of IAP family gene expression and interactions of IAPs with other proteins, this IAP-dependent threshold for caspase-induced apoptosis could be varied to suit various physiological needs. Dysregulation of these normal control mechanisms then could be a contributor to various diseases characterized by excessive (ischemia, AIDS, SMA) or inadequate (cancer, autoimmunity) cell death.