Die Another Day: Inhibition of Cell Death Pathways by Cytomegalovirus

Abstract

Multicellular organisms have evolved multiple genetically programmed cell death pathways that are essential for homeostasis. The finding that many viruses encode cell death inhibitors suggested that cellular suicide also functions as a first line of defence against invading pathogens. This theory was confirmed by studying viral mutants that lack certain cell death inhibitors. Cytomegaloviruses, a family of species-specific viruses, have proved particularly useful in this respect. Cytomegaloviruses are known to encode multiple death inhibitors that are required for efficient viral replication. Here, we outline the mechanisms used by the host cell to detect cytomegalovirus infection and discuss the methods employed by the cytomegalovirus family to prevent death of the host cell. In addition to enhancing our understanding of cytomegalovirus pathogenesis we detail how this research has provided significant insights into the cross-talk that exists between the various cell death pathways.

Keywords: HCMV; MCMV; apoptosis; necroptosis; necrosis; vIBO; vICA; vIRA; vMIA.

Figure 1

Inhibition of apoptosis by cytomegalovirus (CMV). The viral mitochondria-localized inhibitor of apoptosis (vMIA) and the viral inhibitor of BAK oligomerization (vIBO) inhibit mitochondrial outer membrane permabilization and release of proapoptotic factors (such as cytochrome C (cytC)) by interacting with BAX and BAK, respectively. While murine CMV (MCMV) encodes two specific inhibitors, m38.5 and m41.1, human CMV (HCMV) has only one inhibitor, UL37x1. Whether the UL37x1 protein is BAX-specific or inhibits both BAX and BAK remains controversial. The extrinsic apoptosis pathway initiated by death receptor stimulation is blocked by the viral inhibitor of caspase-8 activation (vICA), which is encoded by the HCMV UL36 and the MCMV M36 gene, respectively. FasL: Fas ligand; FADD: Fas-associated death domain protein; RIPK1: receptor interacting protein kinase-1; TNFα: tumour necrosis factor α; TNFR1: TNF receptor 1; TRADD: TNFR1-associated death domain protein; t-BID: truncated BH3-interacting domain death agonist; APAF1: apoptotic protease activating factor 1.

Figure 2

Inhibition of necroptosis by MCMV. Induction of programmed necrosis (necroptosis) involves activation of RIPK3 and mixed lineage kinase domain-like (MLKL). The viral inhibitor of RIP activation (vIRA), encoded by the MCMV M45 gene, contains a RIP homotypic interaction motif (RHIM) and inhibits RHIM-dependent activation of RIPK3 by RIPK1, DAI/ZBP1, or TRIF. Death receptor-induced necroptosis requires caspase-8 inhibition, e.g., by vICA. LPS: lipopolysaccharide.