The Rubella Virus Capsid Is an Anti-Apoptotic Protein that Attenuates the Pore-Forming Ability of Bax

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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. Among the variety of defense systems employed by mammalian cells to combat virus infection, apoptosis or programmed cell death is the most drastic response. Some large DNA viruses encode proteins whose sole function is to block apoptosis. Conversely, very little is known about whether RNA viruses encode analogous proteins. In many cases, RNA viruses are able to replicate before cell death occurs, which may be one reason why so little thought has been given to this topic. However, a number of RNA viruses, some of which are important human pathogens, have slow replication cycles and it stands to reason that they must block apoptosis during this time period. Here we show that the multifunctional capsid protein of Rubella virus is a potent inhibitor of apoptosis. Data from reverse genetic experiments suggest that the anti-apoptotic function of a virus-encoded protein is important for replication of an RNA virus. We anticipate that other slowly replicating RNA viruses may employ similar mechanisms and, as such, these studies have implications for development of novel anti-virals and vaccines.