Mitochondrial Apoptosis and the Peripheral Benzodiazepine Receptor

Viruses mercilessly exploit their host cells to guarantee their own proliferation and propagation. To achieve this goal, many viruses suppress the apoptotic program, thereby avoiding premature death of the host cell. Indeed, apopto-sis of infected cells may be considered as a pristine defense against infectious pathogens, as illustrated by a simple Gedankenexperiment : if all host cells died immediately after infection, then the virus could not replicate. It is only at late stages of the viral life cycle that some viruses actively induce apoptosis, either in their host cells or, via a variety of different strategies, in immunologically relevant cells, with the specific aim to subvert the host's innate or cognate immune response. As viruses have coevoluted with their host to adapt to particular ecological niches, they have " learned " to target strategic processes in their host cell's biology. One fascinating example is now provided by the poxvirus that causes myxomatosis, a lethal disease which has been eradicating entire populations of rabbits. Myxoma virus codes for a protein designated M11L, which, as shown in this issue (1), inhibits host cell apoptosis by acting on the peripheral-type benzodiazepine receptor (PBR). M11L: An Antiapoptotic Virulence Factor Targeted to the Mi-tochondrial PBR. The 18-kD M11L protein is a major vir-ulence factor for myxomatosis. In vivo, M11L knockout viruses provoke a greatly reduced mortality and induce more vigorous, presumably host-protective inflammatory reactions than pathogenic wild-type strains. In vitro, M11L knockout viruses cause accelerated apoptosis in infected rabbit lymphocytes or monocytes, as compared with wild-type controls (2, 3), suggesting that M11L acts as an inhibi-tor of apoptosis. Overexpression of M11L suffices to inhibit apoptosis induced via a variety of nonviral inducers suggesting that it acts as general rather than a virus-or signal-specific apoptosis inhibitor (1). It is important to note that M11L is not the only anti-apoptotic virulence factor encoded by myxoma virus. Additional antiapoptotic proteins include (a) Serp2, a putative caspase inhibitor, (b) T2, a TNF receptor homologue which neutralizes proapoptotic TNF ␣ , (c) myxoma virus leukemia-associated protein, which down-regulates Fas/ CD95 and class I molecules, and (d) T7, an interferon ␥ receptor homologue which inhibits proapoptotic interferon ␥ (4, 5). Myxoma virus relies on a complex strategy to intercept apoptotic and cytotoxic insults to virus-infected cells, because deletion of one single gene among these apoptosis inhibitors suffices to attenuate the virus. The M11L protein targets mitochondria via a 25 amino acid …