Cell death suppression by cytomegaloviruses

Goldmacher, V S

doi:10.1007/s10495-005-0800-z

Cited by 62 publications

(57 citation statements)

References 147 publications

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“…This could reflect the difference in Bak/Bax dependence between cell lines, as has been reported previously. 33 We found that Bak knockdown in uninfected and DF1L-infected cells protects equally well from apoptosis, as infection with WR virus protects the control knockdown cells (Figure 8d). We therefore favour that acute depletion of Bak lowers the total Bak/Bax burden on the cells.…”

Section: F1l Binds Bak To Inhibit Apoptosismentioning

confidence: 66%

Interaction of F1L with the BH3 domain of Bak is responsible for inhibiting vaccinia-induced apoptosis

et al. 2006

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Apoptosis represents an important cellular defence mechanism against viral pathogens by virtue of its ability to remove infected cells. Consequently, many viruses have developed numerous strategies to prevent or delay host cell apoptosis in order to achieve productive replication. Here we report that deletion of the F1L gene from the vaccinia genome results in increased apoptosis during infection. We demonstrate that F1L, which has no sequence homology to Bcl-2 family members, inhibits apoptosis at the level of mitochondria by binding to Bak. As a consequence, F1L prevents Bak activation, oligomerization and interaction with active Bax, all critical steps in the induction of apoptosis. We demonstrate that residues 64-84 of F1L interact directly with the Bcl-2 homology domain 3 (BH3) domain of Bak. This region of F1L has limited sequence similarity to known Bak-interacting BH3 domains. We also find that such additional BH3-like domains exist in the vaccinia genome. We conclude that F1L uses this specific, BH3-like domain to bind and inhibit Bak at the mitochondria.

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Section: F1l Binds Bak To Inhibit Apoptosismentioning

confidence: 66%

Interaction of F1L with the BH3 domain of Bak is responsible for inhibiting vaccinia-induced apoptosis

et al. 2006

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“…Inhibition can be achieved through indirect mechanisms such as the virus-induced downregulation of death receptor expression (116) or the expression of secreted viral TNF receptor homologs (9), both of which prevent signaling at the cell surface. An important general mechanism viruses use to suppress caspase activation is inhibition of mitochondrial membrane permeabilization, thus preventing or delaying the release of cytochrome c. These approaches utilized by viruses to prevent apoptosis have been reviewed in detail elsewhere (2, 14,17,39,47,61,107,113).…”

Section: Virus-mediated Inhibition Of Caspasesmentioning

confidence: 99%

Viral Subversion of Apoptotic Enzymes: Escape from Death Row

Best

2008

Annu. Rev. Microbiol.

148

119

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To prolong cell viability and facilitate replication, viruses have evolved multiple mechanisms to inhibit the host apoptotic response. Cellular proteases such as caspases and serine proteases are instrumental in promoting apoptosis. Thus, these enzymes are logical targets for virus-mediated modulation to suppress cell death. Four major classes of viral inhibitors antagonize caspase function: serpins, p35 family members, inhibitor of apoptosis proteins, and viral FLICE-inhibitory proteins. Viruses also subvert activity of the serine proteases, granzyme B and HtrA2/Omi, to avoid cell death. The combined efforts of viruses to suppress apoptosis suggest that this response should be avoided at all costs. However, some viruses utilize caspases during replication to aid virus protein maturation, progeny release, or both. Hence, a multifaceted relationship exists between viruses and the apoptotic response they induce. Examination of these interactions contributes to our understanding of both virus pathogenesis and the regulation of apoptotic enzymes in normal cellular functions.

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“…vMIA contains two domains, a Nterminal mitochondrial localization sequence (MLS, aa 5-34) that does not undergo proteolytical removal (Mavinakere et al, 2006) and the Bax-binding domain (BBD, aa 115-147) (Arnoult et al, 2004;Poncet et al, 2004). These domains are together necessary and sufficient for vMIA-mediated cytoprotection, as determined by deletion mapping (Goldmacher et al, 1999(Goldmacher et al, , 2005, and are highly conserved among all tested clinical viral isolates (Hayajneh et al, 2001). The three-dimensional structure of vMIA has not been yet established by either NMR or crystal structure analysis.…”

Section: Introductionmentioning

confidence: 99%

Structure–function analysis of the interaction between Bax and the cytomegalovirus-encoded protein vMIA

et al. 2007

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The viral mitochondrial inhibitor of apoptosis (vMIA) encoded by the human cytomegalovirus exerts cytopathic effects and neutralizes the proapoptotic endogenous Bcl-2 family member Bax by recruiting it to mitochondria, inducing its oligomerization and membrane insertion. Using a combination of computational modeling and mutational analyses, we addressed the structure-function relationship of the molecular interaction between the protein Bax and the viral antiapoptotic protein vMIA. We propose a model in which vMIA exhibits an overall fold similar to Bcl-X L . In contrast to Bcl-X L , however, this predicted conformation of vMIA does not bind to the BH3 domain of Bax and rather engages in electrostatic interactions that involve a stretch of amino acids between the BH3 and BH2 domains of Bax and an a-helical domain located within the previously defined Bax-binding domain of vMIA, between the putative BH1-like and BH2-like domains. According to this model, vMIA is likely to bind Bax preferentially in its membraneinserted conformation. The capacity of vMIA to cause fragmentation of the mitochondrial network and disorganization of the actin cytoskeleton is independent of its Baxbinding function. We found that D131-147 vMIA mutant, which lacks both the Bax-binding function and cell-death suppression but has intact mitochondria-targeting capacity, is similar to vMIA in its ability to disrupt the mitochondrial network and to disorganize the actin cytoskeleton. vMIAD131-147 is a dominant-negative inhibitor of the antiapoptotic function of wild-type vMIA. Our experiments with vMIAD131-147 suggest that vMIA forms homooligomers, which may engage in cooperative and/or multivalent interactions with Bax, leading to its functional neutralization.

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Cell death suppression by cytomegaloviruses

Cited by 62 publications

References 147 publications

Interaction of F1L with the BH3 domain of Bak is responsible for inhibiting vaccinia-induced apoptosis

Interaction of F1L with the BH3 domain of Bak is responsible for inhibiting vaccinia-induced apoptosis

Viral Subversion of Apoptotic Enzymes: Escape from Death Row

Structure–function analysis of the interaction between Bax and the cytomegalovirus-encoded protein vMIA

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