Viruses and apoptosis

Abstract

Apoptosis, or programmed cell death, is essential in development and homeostasis in multi-cellular organisms. It is also an important component of the cellular response to injury. Many cells undergo apoptosis in response to viral infection, with a consequent reduction in the release of progeny virus. Viruses have therefore evolved multiple distinct mechanisms for modulating host cell apoptosis. Viruses may interfere with either the highly conserved 'effector' mechanisms of programmed cell death or regulatory mechanisms specific to mammalian cells. In addition to conferring a selective advantage to the virus, the capacity to prevent apoptosis has an essential role in the transformation of the host cell by oncogenic viruses. This article provides a focussed review of apoptosis and illustrates how the study of viruses has informed our understanding of this process. Selected mechanisms by which viral gene products interfere with cell death are discussed in detail and used to illustrate the general principles of the interactions between viruses and apoptosis.

Figure 1

The selective permeabilization of mitochondrial membranes (mitochondrial membrane permeabilization, MMP), is a key event in the induction of apoptosis. Members of the Bcl-2 family play an important role in regulating this process and may either be resident in the membrane as part of the permeability transition pore complex (PTPC) or translocate to the mitochondria in response to specific signals. The figure illustrates selected events that promote MMP, many of which can be modulated by viral proteins.

Figure 2

The structure of Bcl-2 family members. Group I proteins (Bcl-2, Bcl-x_L) contain four conserved Bcl-2 homology (BH) domains (BH1–4) and a C-terminal hydrophobic transmembrane sequence (TM). These proteins are all antiapoptotic. In contrast, Group II proteins lack the BH4 domains and promote apoptosis. Group III proteins contain only a BH3 domain and most members of this group are otherwise unrelated to members of the Bcl-2 family. Adenovirus 19K protein is an example of a group III protein. In contrast, the v-Bcl-2 proteins found in Epstein-Barr virus and HHV-8 appear to be divergent homologues of Bcl-2 and do not contain a BH3 domain.

Figure 3

Signal transduction in the CD95 pathway. Activated, trimerized CD95 receptor forms a death inducing signalling complex (DISC) with adapter molecules FADD and procaspase-8. FADD binds to CD95 via a domain known as the death domain (DD) present in both proteins. Procaspase-8 is recruited by homologous interaction with a second domain in FADD, the death effector domain (DED). The formation of DISC leads to the release of activated caspase-8 in the form of a heterotetramer. Thereafter, caspase-8 either acts directly on caspase-3 (CASP-3) in type I cells or activates Bid to induce MMP and formation of a functional apoptosome in type II cells. Viral and cellular FLIP proteins inhibit the formation of DISC.