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XIAP Activity Dictates Apaf-1 Dependency for Caspase 9 Activation ^,

Division of Cell and Molecular Biology, Toronto General Research Institute-University Health Network, 67 College Street, Toronto, Ontario, Canada M5G 2M1,¹ Departments of Medical Biophysics,² Laboratory Medicine and Pathobiology,³ Medicine,⁴ Immunology, University of Toronto,⁵ The Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, 620 University Avenue, Toronto, Ontario, Canada M5G 2C1⁶

Received 31 January 2007/ Returned for modification 30 March 2007/ Accepted 4 June 2007

The current model for the intrinsic apoptotic pathway holds that mitochondrial activation of caspases in response to cytotoxic drugs requires both Apaf-1-induced dimerization of procaspase 9 and Smac/Diablo-mediated sequestration of inhibitors of apoptosis proteins (IAPs). Here, we showed that either pathway can independently promote caspase 9 activation in response to apoptotic stimuli. In drug-treated Apaf-1^–/– primary myoblasts, but not fibroblasts, Smac/Diablo accumulates in the cytosol and sequesters X-linked IAP (XIAP), which is expressed at lower levels in myoblasts than in fibroblasts. Consequently, caspase 9 activation proceeds in Apaf-1^–/– myoblasts; concomitant ablation of Apaf-1 and Smac is required to prevent caspase 9 activation and the onset of apoptosis. Conversely, in stimulated Apaf-1^–/– fibroblasts, the ratio of XIAP to Smac/Diablo is high compared to that for myoblasts and procaspase 9 is not activated. Suppressing XIAP with exogenous Smac/Diablo or a pharmacological inhibitor can still induce caspase 9 in drug-treated Apaf-1-null fibroblasts. Thus, caspase 9 activation in response to intrinsic apoptotic stimuli can be uncoupled from Apaf-1 in vivo by XIAP antagonists.

Published ahead of print on 11 June 2007.

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