Proteasome activator REGgamma enhances coxsackieviral infection by facilitating p53 degradation.
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.
Gao
Guang
G
James Hogg Research Center, Providence Heart and Lung Institute, University of British Columbia, St. Paul's Hospital, 1081 Burrard St., Vancouver, BC, Canada V6Z 1Y6.
Wong
Jerry
J
Zhang
Jingchun
J
Mao
Ivy
I
Shravah
Jayant
J
Wu
Yan
Y
Xiao
Allen
A
Li
Xiaotao
X
Luo
Honglin
H
D021581:Active Transport, Cell Nucleus; D001324:Autoantigens / Q000235:genetics*; D003384:Coxsackievirus Infections / Q000209:etiology*; D003593:Cytoplasm; D029822:Enterovirus B, Human; D005786:Gene Expression Regulation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D034741:RNA, Small Interfering / Q000494:pharmacology; D025842:SUMO-1 Protein / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014779:Virus Replication
D001324:Autoantigens; C099558:Ki antigen; D034741:RNA, Small Interfering; D025842:SUMO-1 Protein; D016159:Tumor Suppressor Protein p53; D046988:Proteasome Endopeptidase Complex