Self-regulation of BAX-induced cell death

Denis E Reyna,Evripidis Gavathiotis

doi:10.18632/oncotarget.11948

Denis E Reyna, Evripidis Gavathiotis

Open Access

https://doi.org/10.18632/oncotarget.11948

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Abstract

Apoptosis, a form of programmed cell death, is a process in multicellular organisms responsible for normal tissue development and homeostasis. The intrinsic pathway of apoptosis is principally regulated by protein-protein interactions within the BCL-2 family of proteins, which can prevent or promote mitochondrial dysfunction. There are over twenty BCL-2 family proteins grouped together based on their functional and structural similarities. Specifically, family members are divided into anti-apoptotic and pro-apoptotic proteins and posses up to four BCL-2 Homology (BH) domains, namely BH1, BH2, BH3 and BH4. The BH3 domain is the most conserved and serves as the key domain to mediate protein-protein interactions between the members. Upon a variety of apoptotic stimuli, pro-apoptotic protein BAX triggers the intrinsic apoptotic pathway by inducing mitochondrial outer membrane permeabilization and the release of soluble factors important in caspase activation that are required for apoptosis. The precise mechanisms of BAX activation and inhibition are essential to the understanding of the mitochondrial cell death pathway in physiological and pathological states. Pro-apoptotic BAX resides primarily in the cytosol in a conformation that requires activation for inducing apoptosis [1]. Interaction of cytosolic BAX with the BH3 domain of BH3-only proteins, such as BIM, induces structural conformational changes on BAX enabling it to translocate to the mitochondria and homo-oligomerize into a deadly membrane pore [2, 3]. Specifically, structural studies have identified that BH3-binding to the N-terminal activation site stimulates conformational changes leading to the release of the C-terminal helix α9 from the hydrophobic groove, which facilitates mitochondrial anchoring and oligomerization of BAX [4, 5]. Therefore, two structural regions critical to BAX activation are available for BAX modulation in the cytosol. Because BAX activation requires the availability of its activators, it is not understood if and how BAX can regulate its activation in the presence of apoptotic insults. In search of additional mechanisms that keep cytosolic BAX inactive and regulate its activation, we investigated the hypothesis that other proteins may interact with BAX in the cytosol. For several cell lines that are under non-apoptotic stress, we isolated cytosolic fractions Commentary: Autophagy and Cell Death

Highlights

Apoptosis, a form of programmed cell death, is a process in multicellular organisms responsible for normal tissue development and homeostasis
Determination of the fulllength crystal structure of BAX revealed that BAX dimers formed an asymmetric conformation with intermolecular interactions involving the N-terminal BAX activation site of one BAX monomer and the C-terminal surface, including C-terminal helix α9, of the other BAX monomer [6]
Because BAX activation by the BH3 binding to the N-terminal activation site induces a conformational change that leads to C-terminal helix α9 release [7], the structural findings suggest that BAX dimer forms an autoinhibited conformation that resists BH3 activation and conformational displacement of helix α9, providing stabilization of the inactive BAX conformation

Summary

Introduction

A form of programmed cell death, is a process in multicellular organisms responsible for normal tissue development and homeostasis. In search of additional mechanisms that keep cytosolic BAX inactive and regulate its activation, we investigated the hypothesis that other proteins may interact with BAX in the cytosol. We found that in some cells cytosolic BAX eluted as dimers or both as monomers and dimers [6].

Results

Conclusion