Regulation of BAX/BAK-Dependent Cell Death

Washington University, Saint Louis MO

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Abstract

DESCRIPTION (provided by applicant): The BCL-2 family of proteins, consisting of both anti-apoptotic and pro-apoptotic members, constitutes a crucial checkpoint in the cell death pathway. These members are essential for maintenance of major organ homeostasis, and mutations affecting them can result in cancer. The "BH3-only" molecules activate "multi-domain" pro-apoptotic members BAX and BAK to trigger a mitochondrion-dependent cell death pathway, which both releases cytochrome c to activate caspases and initiates caspase-independent mitochondrial dysfunction. Conversely, anti-apoptotic BCL-2/BCL-XL sequesters translocated "BH3-only" molecules in stable mitochondrial complexes, thus preventing the activation of BAX/BAK. Loss of function studies revealed that the absence of pro-apoptotic BAX and BAK creates a profound block in apoptosis triggered by diverse death signals initiated at multiple sites including plasma membrane, nucleus, and endoplastic reticulum. Thus, activation of a "multidomain" pro-apoptotic member, BAX or BAK, appears to be an essential gateway to the mitochondria-mediated cell death program. What maintains BAK in an inactive conformation at mitochondria and precisely how it is activated to manifest in cell death are still unclear. I reasoned that an additional death regulatory protein might exist and have identified a BAK-interacting protein that only interacts with the inactive conformer of BAK and is displaced form BAK upon its activation by "BH3-only" molecules. Further characterization of this novel participant (entitled X) and its precise effects will further understanding of how "BH3-only" proteins activate BAK and the mitochondrial death pathway. In this context, I propose the following specific aims: (1) Dissect the mechanisms by which "multidomain" pro-apoptotic BAX and BAK mediate mitochondrial dysfunction and cell death; (2) Determine the role of BAK-interacting protein (X) in regulating apoptosis.