Bcl-2 family members: dual regulators of apoptosis and autophagy

Abstract

The essential autophagy protein and haplo-insufficient tumor suppressor, Beclin 1, interacts with several cofactors (Ambra1, Bif-1, UVRAG) to activate the lipid kinase Vps34, thereby inducing autophagy. In normal conditions, Beclin 1 is bound to and inhibited by Bcl-2 or the Bcl-2 homolog Bcl-X(L). This interaction involves a Bcl-2 homology 3 (BH3) domain in Beclin 1 and the BH3 binding groove of Bcl-2/Bcl-X(L). Other proteins containing BH3 domains, called BH3-only proteins, can competitively disrupt the interaction between Beclin 1 and Bcl-2/Bcl-X(L) to induce autophagy. Nutrient starvation, which is a potent physiologic inducer of autophagy, can stimulate the dissociation of Beclin 1 from its inhibitors, either by activating BH3-only proteins (such as Bad) or by posttranslational modifications of Bcl-2 (such as phosphorylation) that may reduce its affinity for Beclin 1 and BH3-only proteins. Thus, anti-apoptotic Bcl-2 family members and pro-apoptotic BH3-only proteins may participate in the inhibition and induction of autophagy, respectively. This hitherto neglected crosstalk between the core machineries regulating autophagy and apoptosis may redefine the role of Bcl-2 family proteins in oncogenesis and tumor progression.

Figure 1

The Beclin 1 interactome in human cells and possible mechanisms underlying the regulation of its autophagy function. Beclin 1 binds to the Class III phosphatidylinositol kinase, Vps34, which is associated with the myristoylated, membrane-anchored kinase, Vps15. The lipid kinase activity of the multiprotein Beclin 1/Vps34 complex converts phosphatidylinositol into phosphatidylinositol-3-phosphate (depicted as yellow circles), which is involved in the nucleation of pre-autophagosomal structures. Beclin 1 interacts with several coactivators including UVRAG, Ambra1 and Bif-1, as well as with the inhibitors, Bcl-2 and Bcl-X_L. Shown here are two mechanisms for disrupting the interaction between Beclin 1 and Bcl-2 or Bcl-X_L, and thereby activating autophagy: (1) Proteins that contain BH3 domains or small molecules that mimic BH3 domains can bind to the BH3-binding groove of Bcl-2 or Bcl-X_L and competitively disrupt the interaction between Bcl-2 or Bcl-X_L and Beclin 1. This leads to the de-inhibition of the lipid kinase activity of the class III phosphatidylinositol-3-kinase Vps34 and autophagy induction. (2) C-Jun-N’-terminal kinase 1 (JNK1)-mediated phosphorylation of Bcl-2 during starvation can disrupt its interaction with Beclin 1, leading to autophagy induction.

Figure 2

Beclin 1 BH3 domain bound to the hydrophobic surface groove of Bcl-X_L (A) or Bcl-2 (B). The molecular surface of Bcl-2/Bcl-X_L is color-coded by atom type: yellow represents carbon, blue represents nitrogen, red represents oxygen, and green represents sulfur. The Beclin 1 BH3 helix is shown in gray ribbon. Conserved residues within the BH3 helix, L112, L116, D121 and F123, that are involved in binding to the hydrophophic groove of Bcl-2 homologs are represented in atomic detail with atoms colored as above, except that carbon is depicted in grey. This figure demonstrates that conformational changes are required to accommodate a BH3 domain in the hydrophobic grooves of Bcl-2/Bcl-X_L. The crystallographic structure of the Beclin 1 BH3 domain bound to Bcl-X_L has been previously determined whereas in (B), the Beclin 1 BH3 domain is modeled into a molecular surface representation of Bcl-2, based on a structural superposition of Bcl-2 and Bcl-X_L.