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.
Highlights
Rubella virus (RV) is an enveloped positive strand RNA virus in the family Togaviridae and is the sole member of the genus Rubivirus
We report that the capsid protein blocks apoptosis in RV infected cells most likely to allow sufficient time for virus replication
Cells infected with RV are resistant to apoptosis We reasoned that in order for RV replication and virion secretion to increase through 48 hours and beyond, programmed cell death must be inhibited during this period
Summary
Rubella virus (RV) is an enveloped positive strand RNA virus in the family Togaviridae and is the sole member of the genus Rubivirus (reviewed in [1]). A number of studies suggest that viral persistence may underlie some of the most serious aspects of infection including congenital Rubella syndrome and arthritis [2,3,4,5,6]. Virus infection induces clustering of mitochondria in the perinuclear region as well as formation of electron-dense plaques between apposing mitochondrial cisternae: structures that have been termed confronting membranes [8,9]. The function of these structures is not known but expression of capsid protein in the absence of other RV proteins is sufficient to induce their formation [10]. It is well documented that togavirus infection often results in apoptotic death of mammalian cells (reviewed in [14,15]) and to
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