Research Article: Viral Control of Mitochondrial Apoptosis

Date Published: May 30, 2008

Publisher: Public Library of Science

Author(s): Lorenzo Galluzzi, Catherine Brenner, Eugenia Morselli, Zahia Touat, Guido Kroemer, B. Brett Finlay.


Throughout the process of pathogen–host co-evolution, viruses have developed a battery of distinct strategies to overcome biochemical and immunological defenses of the host. Thus, viruses have acquired the capacity to subvert host cell apoptosis, control inflammatory responses, and evade immune reactions. Since the elimination of infected cells via programmed cell death is one of the most ancestral defense mechanisms against infection, disabling host cell apoptosis might represent an almost obligate step in the viral life cycle. Conversely, viruses may take advantage of stimulating apoptosis, either to kill uninfected cells from the immune system, or to induce the breakdown of infected cells, thereby favoring viral dissemination. Several viral polypeptides are homologs of host-derived apoptosis-regulatory proteins, such as members of the Bcl-2 family. Moreover, viral factors with no homology to host proteins specifically target key components of the apoptotic machinery. Here, we summarize the current knowledge on the viral modulation of mitochondrial apoptosis, by focusing in particular on the mechanisms by which viral proteins control the host cell death apparatus.

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The sacrifice, via programmed cell death (PCD), of infected cells represents the most primordial response of multicellular organisms to viruses. This response is common to all metazoan phyla, including plants (which lack an immune system based on mobile cells) (Text S2, [S1]). In mammals, microbial invasion does not only trigger PCD of infected cells but also elicits an immune reaction. This is hierarchically organized in a first-line response provided by innate immune effectors (e.g., infiltrating phagocytes and natural killer cells) [S2], followed by the activation of adaptive immunity, mediated by T and B lymphocytes [S3]. Importantly, other layers of defense exist to prevent viral replication and spread [S2]. For instance, in invertebrates like Drosophyla melanogaster (as well as in plants), a prominent antiviral mechanism is provided by RNA interference (RNAi) [S4]. Although the RNAi pathway is preserved in mammals, it has presumably been superseded in its antiviral role by the extremely potent interferon system, as well as by a number of additional mechanisms [S5]. Such a multivariate antiviral response is designed to recognize virions, virus-infected cells, and virus-induced signals of stress (including cell death) to eliminate the pathogen (together with the host cell) and to elicit immunological memory [S6]. Thus, the co-evolution between host and virus has forced the latter to develop strategies for modulating host cell PCD and/or for avoiding immunogenic cell death.

The abundant presence of the voltage-dependent anion channel (VDAC) renders OM freely permeable to solutes and small metabolites up to approximately 5 kDa. This cutoff ensures that soluble proteins are retained in the IMS under normal circumstances. The apoptosis-associated drastic increase in OM permeability may originate at the OM itself by means of multiple mechanisms, including (1) the assembly of large homo- or hetero-multimeric channels, allowing for the release of IMS proteins, by proapoptotic pore-forming proteins of the Bcl-2 family (e.g., Bax, Bak) [10,11;S53,S54]; (2) the destabilization of the lipid bilayer mediated by proapoptotic Bcl-2 family members (e.g., Bax, truncated Bid, i.e., tBid), which results in the priming of mitochondria for the release of IMS proteins [S55–S58]; and (3) the induction of the so-called mitochondrial permeability transition (MPT) at the IM, following the interaction between Bax (or tBid) and components of the permeability transition pore complex (PTPC) at the OM [12;S59–S63]. In this latter case, MMP begins and ends at the OM, yet is mediated by an event taking place mainly at the IM, i.e., MPT (see the section “MMP Regulation by the PTPC” for further details). Independently from the specific mechanisms that activate MMP, the Bcl-2 family of proteins exerts a major regulation of this process [S64].

MMP may originate at the IM due to the activation of the PTPC, a large multiprotein structure assembled at the contact sites between OM and IM. This applies in particular to cell death models characterized by enhanced Ca2+ fluxes and disproportionate ROS generation [S98]. PTPC activation provokes a sudden increase in the IM permeability to solutes of low molecular weight (i.e., MPT), which leads to the unregulated entry of water and osmotic swelling of the mitochondrial matrix. In turn, this may result in the physical rupture of the OM, because the surface area of the IM (with its folded cristae) largely exceeds that of the OM [S63,S98,S99]. In the context of MPT-derived MMP, Δψm dissipates before OM is permeabilized and IMS are released (Figure 2) [S63]. Although its exact molecular composition remains elusive, numerous independent studies suggest that the PTPC might result from the association of multiple proteins, including ANT (in the IM) and VDAC (in the OM), in the context of a dynamic interaction with mitochondrial matrix proteins (e.g., cyclophilin D [CypD]), IMS proteins (e.g., creatine kinase [CK]), OM proteins (e.g., peripheral-type benzodiazepine receptor [PBR]), as well as with cytosolic factors (e.g., hexokinase isoforms) (for recent reviews, see [S63,S100,S101]). Nevertheless, genetic studies performed in the murine system suggest that all the aforementioned components of the PTPC, most of which exist in multiple isoforms, are either dispensable for cell death or preferentially participate in necrotic pathways (rather than in apoptosis) [19–21;S102].

During the last decade, numerous viral proteins have been reported to modulate (either positively or negatively, either in a direct or indirect fashion) the apoptotic response of host cells to infection (Figure 3, Tables 1 and 2) [7;S42]. With regard to this, viral factors can be classified into one of the four following subgroups: proapoptotic proteins (1) that insert into mitochondrial membranes and hence trigger MMP through the action of amphipathic α-helical domains or (2) that promote MMP indirectly, through the activition of host-encoded factors (Table 1), and antiapoptotic modulators (3) that exhibit sequence and/or structural similarity to multidomain BH1-4 members of the Bcl-2 family (so-called viral Bcl-2 proteins [vBcl-2s]) or (4) that inhibit apoptosis via other mechanisms (Table 2). Notably, some viral proteins exhibit mixed apoptosis-modulatory functions, and hence cannot be unambiguously classified into one of the aforementioned groups.

While the induction of host cell apoptosis may favor viral dissemination at late stages of infection, it is vital for viruses to inhibit PCD at early steps of the infectious cycle, thereby avoiding premature cell death and allowing the virus to replicate. Thus, viruses have developed a battery of Bcl-2 homologs by which they mimic the major antiapoptotic system of host cells (for a recent review, see [S215]). In some instances, such vBcl-2s fail to show significant sequence similarity with their mammalian counterparts, yet exhibit striking structural resemblance. Finally, a number of viral factors inhibit apoptosis via other mechanisms, which do not directly involve the Bcl-2 system (Table 2).

We have reviewed the cellular impact of viral infection on cell fate via modulation of mitochondrial apoptosis. While specific cellular and molecular mechanisms have been elucidated for a number of individual proteins (e.g., Vpr, vMIA), a clear scheme of the integrated effects resulting from the expression of whole virus genomes has only recently begun to emerge from transcriptomics and proteomics analyses (for a review, see [100]). Future studies will have to take into account the variability of the host cell and its microenvironmental context (e.g., local inflammation, oxidative stress) as key factors susceptible to modulating the response to specific pathogens. This will undoubtedly be instrumental for the prediction of the general consequences of viral infections, as well as for a more accurate identification of novel therapeutic targets designed to eradicate infectious diseases.

A complete list of accession numbers (UniProtKB/Swiss-Prot knowledgebase, for the proteins discussed in this manuscript can be found online in Text S1.