Differential function and expression of the viral inhibitor of caspase 8-induced apoptosis (vICA) and the viral mitochondria-localized inhibitor of apoptosis (vMIA) cell death suppressors conserved in primate and rodent cytomegaloviruses

McCormick, A. Louise; Skaletskaya, Anna; Barry, Peter A.; Mocarski, Edward S.; Goldmacher, Victor S.

doi:10.1016/j.virol.2003.07.003

Cited by 124 publications

(174 citation statements)

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“…Altogether, these data firmly established that HSV-2 R1, by interacting constitutively and directly with caspase-8, prevents its activation. A similar mechanism of action has been described for vICA, the UL36 gene product of human CMV that is conserved in all CMV genomes sequenced to date [65]. Like HSV R1s, vICA suppresses TNFa-and FasL-induced apoptosis but appears to marginally inhibit cell death induced by cytotoxic drugs activating the mitochondrial apoptosis pathway [7,50].…”

Section: Discussionmentioning

confidence: 56%

The ribonucleotide reductase R1 subunits of herpes simplex virus types 1 and 2 protect cells against TNFα- and FasL-induced apoptosis by interacting with caspase-8

et al. 2010

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We previously reported that HSV-2 R1, the R1 subunit (ICP10; UL39) of herpes simplex virus type-2 ribonucleotide reductase, protects cells against apoptosis induced by the death receptor (DR) ligands tumor necrosis factor-alpha-(TNFa) and Fas ligand (FasL) by interrupting DR-mediated signaling at, or upstream of, caspase-8 activation. Further investigation of the molecular mechanism underlying HSV-2 R1 protection showed that extracellularregulated kinase 1/2 (ERK1/2), phosphatidylinositol 3-kinase (PI3-K)/Akt, NF-jB and JNK survival pathways do not play a major role in this antiapoptotic function. Interaction studies revealed that HSV-2 R1 interacted constitutively with caspase-8. The HSV-2 R1 deletion mutant R1(1-834)-GFP and Epstein-Barr virus (EBV) R1, which did not protect against apoptosis induced by DR ligands, did not interact with caspase-8, indicating that interaction is required for protection. HSV-2 R1 impaired caspase-8 activation induced by caspase-8 over-expression, suggesting that interaction between the two proteins prevents caspase-8 dimerization/activation. HSV-2 R1 bound to caspase-8 directly through its prodomain but did not interact with either its caspase domain or Fas-associated death domain protein (FADD). Interaction between HSV-2 R1 and caspase-8 disrupted FADD-caspase-8 binding. We further demonstrated that individually expressed HSV-1 R1 (ICP6) shares, with HSV-2 R1, the ability to bind caspase-8 and to protect cells against DR-induced apoptosis. Finally, as the long-lived Fas protein remained stable during the early period of infection, experiments with the HSV-1 UL39 deletion mutant ICP6D showed that HSV-1 R1 could be essential for the protection of HSV-1-infected cells against FasL.Keywords FasL Á ICP6 Á ICP10 Á Viral inhibitor of apoptosis Á Caspase-8Electronic supplementary material The online version of this article

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Section: Discussionmentioning

confidence: 56%

The ribonucleotide reductase R1 subunits of herpes simplex virus types 1 and 2 protect cells against TNFα- and FasL-induced apoptosis by interacting with caspase-8

et al. 2010

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“…HCMV inhibitors of apoptosis are conserved in RhCMV. Both the UL36 (viral inhibitor of caspase-8-induced apoptosis, vICA) and UL37 (mitochondria inhibitor of apoptosis, vMIA) homologs in RhCMV were able to prevent Fas-mediated apoptosis in HeLa cells, whereas the MCMV UL37 homolog M37 was not [59]. The IL-10 homolog of CMVs was Wrst identiWed in RhCMV and was shown to be expressed in vivo, targeted by the humoral immune response, and to have [14] and [50] immunosuppressive properties [60,61].…”

Section: Functional Characterizations Of Rhcmv Proteinsmentioning

confidence: 99%

Rhesus CMV: an emerging animal model for human CMV

Powers

Früh

2008

Med Microbiol Immunol

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Human CMV is the predominant infectious cause of congenital birth defects and an opportunistic pathogen in immunosuppressed individuals, including AIDS patients. Most individuals are infected early during their life followed by life-long latent infection. During this latent phase, frequent reactivation and antigen production continue to stimulate the immune system. While the immune response is able to control the virus, it is unable to eradicate it. Moreover, super-infection by diVerent CMV strains has been observed despite a strong immune response. Longterm immune stimulation by CMV has also been implicated in immune senescence and chronic conditions such as atherosclerosis. CMVs are highly species-speciWc and the relatedness of CMV genomes exactly mirrors the relatedness of their hosts. Thus, each CMV species is highly adapted to its respective host species, but is unable to infect other, even closely related hosts. While fascinating from an evolutionary perspective, this host restriction prevents studying HCMV in experimental animals. Exceptions are severely immunocompromised mice, e.g. SCID mice, or SCID/NOD mice, which might allow partial reconstitution of CMV infection in rodents. More practical however, is to study CMVs in their natural host, e.g. murine, rat or guinea pig CMVs. However, while these small animal models have many advantages, such as the availability of inbred animals as well as lower cost, the limited homology of the viral genomes with HCMV limits the functional analysis of homologous gene products. The closest relative to HCMV is chimpanzee CMV (CCMV), but this is not a practical animal model since chimps are a protected species, extremely expensive and of very limited availability. In contrast, rhesus macaques are a more widely used experimental animal species and, while more distant than CCMV, rhesus CMV (RhCMV) contains most of the HCMV gene families thus allowing the study of their role in acute and latent CMV infection. In this review we will discuss the current state of developing RhCMV as a model for HCMV.

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“…Indeed, the replication of human cytomegalovirus-a widely spread herpesvirus, pathogenic in immunocompromised individuals-relies on the encoded antiapoptotic protein vMIA (viral mitochondrialocalized inhibitor of apoptosis) (8)(9)(10). In contrast with antiapoptotic Bcl-2 members, which inhibit Bax mitochondrial localization, vMIA recruits Bax to mitochondria as part of its apoptotic inhibitory activity (11).…”

mentioning

confidence: 99%

Structural mechanism of Bax inhibition by cytomegalovirus protein vMIA

Edlich

Bermejo

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The human protein Bax sits at a critical regulatory junction of apoptosis, or programmed cell death. Bax exists in equilibrium between cytosolic and mitochondria-associated forms that shifts toward the latter when Bax is activated by proapoptotic proteins. Activated Bax changes conformation, inserts into the mitochondrial outer membrane (MOM), oligomerizes, and induces MOM permeabilization, causing the release of cytochrome c, which effectively commits the cell to die. Because apoptosis is also a basic defense mechanism against invading pathogens, many viruses have developed counteractive measures. Such is the case of human cytomegalovirus, the replication of which hinges on vMIA (viral mitochondria-localized inhibitor of apoptosis), a virus-encoded protein with a unique, albeit poorly understood antiapoptotic activity by which it binds and recruits Bax to mitochondria. Here we show, via the structure determination of the complex between Bax and a peptide comprising vMIA's Bax-binding domain, that vMIA contacts Bax at a previously unknown regulatory site. Notably, using full-length vMIA, the structure is independently confirmed by assays in human cells that measure Bax subcellular localization and cytochrome c release. Mutants that disrupt key intermolecular interactions disfavor vMIA's mitochondrial recruitment of Bax, and increase cytochrome c release upon apoptosis induction. In a more stringent test, an engineered binding interface that achieves wild-type-like charge complementarity, although in a reversed fashion, recovers wild-type behavior. The structure suggests that by stabilizing key elements in Bax needed to unravel for its MOM insertion and oligomerization, vMIA prevents these important steps in apoptosis.

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Differential function and expression of the viral inhibitor of caspase 8-induced apoptosis (vICA) and the viral mitochondria-localized inhibitor of apoptosis (vMIA) cell death suppressors conserved in primate and rodent cytomegaloviruses

Cited by 124 publications

References 54 publications

The ribonucleotide reductase R1 subunits of herpes simplex virus types 1 and 2 protect cells against TNFα- and FasL-induced apoptosis by interacting with caspase-8

The ribonucleotide reductase R1 subunits of herpes simplex virus types 1 and 2 protect cells against TNFα- and FasL-induced apoptosis by interacting with caspase-8

Rhesus CMV: an emerging animal model for human CMV

Structural mechanism of Bax inhibition by cytomegalovirus protein vMIA

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