New EMBO members' review: viral and bacterial proteins regulating apoptosis at the mitochondrial level

Abstract

Mitochondrial membrane permeabilization (MMP) is a critical step of several apoptotic pathways. Some infectious intracellular pathogens can regulate (induce or inhibit) apoptosis of their host cells at the mitochondrial level, by targeting proteins to mitochondrial membranes that either induce or inhibit MMP. Pathogen-encoded mitochondrion-targeted proteins may or may not show amino acid sequence homology to Bcl-2-like proteins. Among the Bcl-2-unrelated, mitochondrion-targeted proteins, several interact with the voltage-dependent anion channel (VDAC) or with the adenine nucleotide translocator (ANT). While VDAC-targeted proteins show homology to VDAC/porin, ANT-targeted proteins possess relatively short cationic binding domains, which may facilitate insertion into the negatively charged inner mitochondrial membrane. It may be speculated that such proteins employ pre-existing host-intrinsic mechanisms of MMP control.

Fig. 1. Phases of the apoptotic process with respect to MMP. In the left part of the figure, pro-apoptotic pathways converging on mitochondria are shown. Different apoptogenic molecules act on a variety of tentatively identified mitochondrial receptors (arrows), which in turn regulate MMP. The degradation pathways triggered by MMP are depicted on the right. Apoptosis regulatory proteins encoded by pathogens can either target the signal-transducing pathways upstream of mitochondria or the mitochondrion itself. This has functional consequences. Thus, apoptosis inhibitors acting at the mitochondrial level are likely to have a broader spectrum of cytoprotective action than inhibitors acting on upstream signal. GSH, glutathione; ROS, reactive oxygen species.

Fig. 2. Hypothetical mechanisms of MMP induced by pathogen-encoded proteins targeting the PTPC compounds VDAC or ANT. (A) Effects of PorB from N.gonorrhoeae or HBV-X from hepatitis B virus. Upon interaction with VDAC, these proteins incorporate into the outer membrane, where they form heterotrimers (or perhaps higher-order oligomers) with VDAC. Bcl-2 would prevent the formation of large non-specific pores in the outer membrane by local effects on VDAC, PorB and/or HVB-X. (B) Model of the Vpr–ANT interactions. Vpr crosses the outer membrane through VDAC and then interacts with ANT, and in particular with the second loop of ANT facing the intermembrane space. Bcl-2 would inhibit the binding of Vpr to ANT. The physical interaction between ANT and Vpr would culminate in cooperative channel formation leading to a primary permeabilization of the inner mitochondrial membrane.