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The Rubella virus capsid is an anti-apoptotic protein that attenuates the pore-forming ability of Bax.

Ilkow CS, Goping IS, Hobman TC - PLoS Pathog. (2011)

Bottom Line: The main mechanism of action was specific for Bax as capsid bound Bax and prevented Bax-induced apoptosis but did not bind Bak nor inhibit Bak-induced apoptosis.Intriguingly, interaction with capsid protein resulted in activation of Bax in the absence of apoptotic stimuli, however, release of cytochrome c from mitochondria and concomitant activation of caspase 3 did not occur.Accordingly, we propose that binding of capsid to Bax induces the formation of hetero-oligomers that are incompetent for pore formation.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, University of Alberta, Edmonton, Canada.

ABSTRACT
Apoptosis is an important mechanism by which virus-infected cells are eliminated from the host. Accordingly, many viruses have evolved strategies to prevent or delay apoptosis in order to provide a window of opportunity in which virus replication, assembly and egress can take place. Interfering with apoptosis may also be important for establishment and/or maintenance of persistent infections. Whereas large DNA viruses have the luxury of encoding accessory proteins whose primary function is to undermine programmed cell death pathways, it is generally thought that most RNA viruses do not encode these types of proteins. Here we report that the multifunctional capsid protein of Rubella virus is a potent inhibitor of apoptosis. The main mechanism of action was specific for Bax as capsid bound Bax and prevented Bax-induced apoptosis but did not bind Bak nor inhibit Bak-induced apoptosis. Intriguingly, interaction with capsid protein resulted in activation of Bax in the absence of apoptotic stimuli, however, release of cytochrome c from mitochondria and concomitant activation of caspase 3 did not occur. Accordingly, we propose that binding of capsid to Bax induces the formation of hetero-oligomers that are incompetent for pore formation. Importantly, data from reverse genetic studies are consistent with a scenario in which the anti-apoptotic activity of capsid protein is important for virus replication. If so, this would be among the first demonstrations showing that blocking apoptosis is important for replication of an RNA virus. Finally, it is tempting to speculate that other slowly replicating RNA viruses employ similar mechanisms to avoid killing infected cells.

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Related in: MedlinePlus

Model for how capsid blocks Bax-dependent apoptosis.Apoptotic stimuli can induce a conformational change in Bax, which is followed by stable membrane association and oligomerization. The Bax oligomers serve as pores that faciliate efflux of cytochrome c from the mitochondria to the cytoplasm where it initiates downstream apoptotic signaling through the apoptosome. The RV capsid protein binds to Bax before or after it is translocated to mitochondria. Interaction with capsid is followed a conformational change in Bax and subsequent hetero-oligomer formation. However, the Bax-capsid oligomers do not allow efflux of cytochrome c from the mitochondria and apoptosis is blocked.
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ppat-1001291-g014: Model for how capsid blocks Bax-dependent apoptosis.Apoptotic stimuli can induce a conformational change in Bax, which is followed by stable membrane association and oligomerization. The Bax oligomers serve as pores that faciliate efflux of cytochrome c from the mitochondria to the cytoplasm where it initiates downstream apoptotic signaling through the apoptosome. The RV capsid protein binds to Bax before or after it is translocated to mitochondria. Interaction with capsid is followed a conformational change in Bax and subsequent hetero-oligomer formation. However, the Bax-capsid oligomers do not allow efflux of cytochrome c from the mitochondria and apoptosis is blocked.

Mentions: Although capsid protein may interfere with apoptosis by more than one mechanism, because the Bax-dependent pathway is a critical feature of mitochondrial apoptosis in most human cell types, interfering with the pore-forming ability of this protein is likely the key anti-apoptotic function of capsid protein. Binding of capsid protein to Bax induces a major conformational change, which interestingly, seems to promote activation and oligomerization of Bax. It is not clear if this phenomenon is related to the anti-apoptotic activity of capsid or if it is an inconsequential effect of complex formation with Bax. Figure 14 depicts a model in which capsid protein interferes with formation of functional Bax pores. In some critical aspects, the RV capsid protein may function analogously to the cytomegalovirus accessory protein vMIA, a putative Bcl-2 homolog that forms mixed oligomers with Bax [56]. However, confirmation of this theory is dependent upon determining the structure of the RV capsid protein.


The Rubella virus capsid is an anti-apoptotic protein that attenuates the pore-forming ability of Bax.

Ilkow CS, Goping IS, Hobman TC - PLoS Pathog. (2011)

Model for how capsid blocks Bax-dependent apoptosis.Apoptotic stimuli can induce a conformational change in Bax, which is followed by stable membrane association and oligomerization. The Bax oligomers serve as pores that faciliate efflux of cytochrome c from the mitochondria to the cytoplasm where it initiates downstream apoptotic signaling through the apoptosome. The RV capsid protein binds to Bax before or after it is translocated to mitochondria. Interaction with capsid is followed a conformational change in Bax and subsequent hetero-oligomer formation. However, the Bax-capsid oligomers do not allow efflux of cytochrome c from the mitochondria and apoptosis is blocked.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3040668&req=5

ppat-1001291-g014: Model for how capsid blocks Bax-dependent apoptosis.Apoptotic stimuli can induce a conformational change in Bax, which is followed by stable membrane association and oligomerization. The Bax oligomers serve as pores that faciliate efflux of cytochrome c from the mitochondria to the cytoplasm where it initiates downstream apoptotic signaling through the apoptosome. The RV capsid protein binds to Bax before or after it is translocated to mitochondria. Interaction with capsid is followed a conformational change in Bax and subsequent hetero-oligomer formation. However, the Bax-capsid oligomers do not allow efflux of cytochrome c from the mitochondria and apoptosis is blocked.
Mentions: Although capsid protein may interfere with apoptosis by more than one mechanism, because the Bax-dependent pathway is a critical feature of mitochondrial apoptosis in most human cell types, interfering with the pore-forming ability of this protein is likely the key anti-apoptotic function of capsid protein. Binding of capsid protein to Bax induces a major conformational change, which interestingly, seems to promote activation and oligomerization of Bax. It is not clear if this phenomenon is related to the anti-apoptotic activity of capsid or if it is an inconsequential effect of complex formation with Bax. Figure 14 depicts a model in which capsid protein interferes with formation of functional Bax pores. In some critical aspects, the RV capsid protein may function analogously to the cytomegalovirus accessory protein vMIA, a putative Bcl-2 homolog that forms mixed oligomers with Bax [56]. However, confirmation of this theory is dependent upon determining the structure of the RV capsid protein.

Bottom Line: The main mechanism of action was specific for Bax as capsid bound Bax and prevented Bax-induced apoptosis but did not bind Bak nor inhibit Bak-induced apoptosis.Intriguingly, interaction with capsid protein resulted in activation of Bax in the absence of apoptotic stimuli, however, release of cytochrome c from mitochondria and concomitant activation of caspase 3 did not occur.Accordingly, we propose that binding of capsid to Bax induces the formation of hetero-oligomers that are incompetent for pore formation.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, University of Alberta, Edmonton, Canada.

ABSTRACT
Apoptosis is an important mechanism by which virus-infected cells are eliminated from the host. Accordingly, many viruses have evolved strategies to prevent or delay apoptosis in order to provide a window of opportunity in which virus replication, assembly and egress can take place. Interfering with apoptosis may also be important for establishment and/or maintenance of persistent infections. Whereas large DNA viruses have the luxury of encoding accessory proteins whose primary function is to undermine programmed cell death pathways, it is generally thought that most RNA viruses do not encode these types of proteins. Here we report that the multifunctional capsid protein of Rubella virus is a potent inhibitor of apoptosis. The main mechanism of action was specific for Bax as capsid bound Bax and prevented Bax-induced apoptosis but did not bind Bak nor inhibit Bak-induced apoptosis. Intriguingly, interaction with capsid protein resulted in activation of Bax in the absence of apoptotic stimuli, however, release of cytochrome c from mitochondria and concomitant activation of caspase 3 did not occur. Accordingly, we propose that binding of capsid to Bax induces the formation of hetero-oligomers that are incompetent for pore formation. Importantly, data from reverse genetic studies are consistent with a scenario in which the anti-apoptotic activity of capsid protein is important for virus replication. If so, this would be among the first demonstrations showing that blocking apoptosis is important for replication of an RNA virus. Finally, it is tempting to speculate that other slowly replicating RNA viruses employ similar mechanisms to avoid killing infected cells.

Show MeSH
Related in: MedlinePlus