XIAP: cell death regulation meets copper homeostasis

Abstract

X-linked inhibitor of apoptosis (XIAP), traditionally known as an anti-apoptotic protein, has recently been shown to be involved in copper homeostasis. XIAP promotes the ubiquitination and degradation of COMMD1, a protein that promotes the efflux of copper from the cell. Through its effects on COMMD1, XIAP can regulate copper export from the cell and potentially represents an additional intracellular sensor for copper levels. XIAP binds copper directly and undergoes a substantial conformational change in the copper-bound state. This in turn destabilizes XIAP, resulting in lowered steady-state levels of the protein. Furthermore, copper-bound XIAP is unable to inhibit caspases and cells that express this form of the protein exhibit increased rates of cell death in response to apoptotic stimuli. These events take place in the setting of excess intracellular copper accumulation as seen in copper toxicosis disorders such as Wilson's disease and establish a new relationship between copper levels and the regulation of cell death via XIAP. These findings raise important questions about the role of XIAP in the development of copper toxicosis disorders and may point to XIAP as a potential therapeutic target in these disease states.

Figure 1

The IAP Family Members. Eight mammalian IAPs have been described so far and all are characterized the presence of one or more baculovirus IAP repeat (BIR) domains.

Figure 2

Role of XIAP in the extrinsic and intrinsic cell death signaling pathways. Two different pathways can initiate apoptosis. The death-receptor mediated (extrinsic) pathway involves the activation of caspase-8 following stimulation of the receptor by ligands such as Fas. The mitochondrial (intrinsic) pathway is initiated by a variety of stimuli including DNA damaging agents such as UV and chemotherapy resulting in the mitochondrial release of cytochrome c and subsequent activation of caspase-9. Both pathways converge to activate caspases- 3 and -7, effector caspases responsible for the death of the cell. XIAP regulates both pathways by its ability to directly bind and inhibit caspase-3, -7 and -9. The mitochondrial proteins, Smac and Omi, antagonize the caspase inhibitory properties of XIAP.

Figure 3

Model of copper uptake and metabolism. Copper enters the cell via the high affinity copper transporter, Ctr1. Atox1 is the chaperone responsible for transporting copper to the P-type ATPases 7A and 7B in the trans Golgi network (TGN). The chaperone, CCS, delivers Cu to cytosolic Cu/Zn superoxide dismutase (SOD1), and Cox17, in the mitochondria, delivers Cu to Cytochrome c Oxidase (CcO). The manner in which copper is transported from the cytosol to Cox 17 in the mitochondria has not been fully elucidated. COMMD1 promotes the efflux of copper from the cell, probably via its interaction with ATP7B. XIAP may reduce copper export by acting as an E3 Ubiquitin ligase and promoting the degradation of COMMD1.

Figure 4

Overview of the relationship between copper, XIAP and the apoptotic threshold. Intracellular copper accumulation induces a conformational change of XIAP, which promotes its degradation and decreases its ability to inhibit caspase-3. The net result of these changes is a lowering of the apoptotic threshold and increased cell death in response to apoptotic stimuli. COMMD1 is involved in the efflux of copper from the cell and XIAP regulates it by promoting its ubiquitination and proteosomal degradation.