BH3-only proteins in apoptosis and beyond: an overview

Abstract

BH3-only BCL-2 family proteins are effectors of canonical mitochondrial apoptosis. They discharge their pro-apoptotic functions through BH1-3 pro-apoptotic proteins such as BAX and BAK, while their activity is suppressed by BH1-4 anti-apoptotic BCL-2 family members. The precise mechanism by which BH3-only proteins mediate apoptosis remains unresolved. The existing data are consistent with three mutually non-exclusive models (1) displacement of BH1-3 proteins from complexes with BH1-4 proteins; (2) direct interaction with and conformational activation of BH1-3 proteins; and (3) membrane insertion and membrane remodeling. The BH3-only proteins appear to play critical roles in restraining cancer and inflammatory diseases such as rheumatoid arthritis. Molecules that mimic the effect of BH3-only proteins are being used in treatments against these diseases. The cell death activity of a subclass of BH3-only members (BNIP3 and BNIP3L) is linked to cardiomyocyte loss during heart failure. In addition to their established role in apoptosis, several BH3-only members also regulate diverse cellular functions in cell-cycle regulation, DNA repair and metabolism. Several members are implicated in the induction of autophagy and autophagic cell death, possibly through unleashing of the BH3-only autophagic effector Beclin 1 from complexes with BCL-2/BCL-xL. The Chapters included in the current Oncogene Review issues provide in-depth discussions on various aspects of major BH3-only proteins.

Figure 1

BCL-2 family proteins. Domain structures of representative members of each subfamily are shown.

Figure 2

Domain structure of major mammalian and worm BH3-only proteins. In addition to the BH3 domain, the C-terminal trans-membrane domain (TM), and other membrane targeting hydrophobic sequences are indicated. MTD, indicates mitochondrial targeting domain. The caspase cleavage sites in BID and MCL-1S and the phosphorylation site in the BH3 domain of BAD are indicated.

Figure 3

Domain structure of some BH3-only-like proteins. The BH3 domain and other functional domain(s) in the respective proteins are indicated.

Figure 4

Amino acid sequences of the BH3 domains. The sequences of various BH3-only and BH3-only-like proteins, their accession numbers and amino acid coordinates are indicated. The consensus sequence of BH3 domain is shown in the bottom, Φ represents a hydrophobic residue (Φ₂ is usually leucine); Σ is a small residue (G, A, S), Ζ is usually an acidic residue; and Γ is a hydrophilic residue (N, H, D or Y) (Day et al., 2008).

Figure 5

Models for the apoptotic activity of BH3-only proteins. A. In normal state, BH3-only proteins are present in very low levels in the cytosol or in mitochondrial membrane, most likely in complex with anti-apoptotic BCL-2 family proteins. BAK is shown to be located in mitochondrial membrane in inactive complexes with BH1-4 anti-apoptotic proteins, where as BAX is shown to be in the cytosol or loosely attached to the mitochondrial membrane. B. Different apoptotic stimuli induce significant up-regulation of the BH3-only proteins through transcriptional and post-transcriptional mechanisms. BH3-only proteins then transmit the apoptotic signals to BAX and BAK proteins either through “direct binding/and activation” (1), or “neutralization of BH1-4 proteins and displacement of BAK/BAX” (2). In addition, BH3-only proteins is also shown to induce mitochondrial membrane remodeling/formation of altered microdomains through mitochondrial outer membrane (MOM) insertion and interaction with membrane lipids (e.g., cardiolipin – yellow heads) and/or with other mitochondrial proteins (3). Two classes of BH3-only proteins (that bind with multi domain anti-apoptotic and pro-apoptotic proteins or only with anti-apoptotic proteins) are indicated in red and orange.