Coxsackievirus B3 (CVB3) is a small RNA virus associated with diseases such as
myocarditis,
meningitis, and
pancreatitis. We have previously demonstrated that
proteasome inhibition reduces CVB3 replication and attenuates virus-induced
myocarditis. However, the underlying mechanisms by which the
ubiquitin/
proteasome system regulates CVB replication remain unclear. In this study, we investigated the role of REGγ, a member of the 11S
proteasome activator, in CVB3 replication. We showed that overexpression of REGγ promoted CVB3 replication but that knockdown of REGγ led to reduced CVB3 replication. We further demonstrated that REGγ-mediated p53 proteolysis contributes, as least in part, to the proviral function of REGγ. Although total
protein levels of REGγ remained unaltered after CVB3
infection, virus infection induced a redistribution of REGγ from the nucleus to the cytoplasm, rendering an opportunity for a direct interaction of REGγ with
viral proteins and/or host
proteins (e.g., p53), which controls viral growth and thereby enhances viral infectivity. Further analyses suggested a potential modification of REGγ by SUMO following CVB3
infection, which was verified by both in vitro and in vivo sumoylation assays. Sumoylation of REGγ may play a role in its nuclear export during CVB3
infection. Taken together, our results present the first evidence that the host REGγ pathway is utilized and modified during CVB3
infection to promote efficient viral replication.