Abstract
Replication of many RNA viruses is accompanied by extensive remodeling of intracellular membranes. In poliovirus-infected cells, ER and Golgi stacks disappear, while new clusters of vesicle-like structures form sites for viral RNA synthesis. Virus replication is inhibited by brefeldin A (BFA), implicating some components(s) of the cellular secretory pathway in virus growth. Formation of characteristic vesicles induced by expression of viral proteins was not inhibited by BFA, but they were functionally deficient. GBF1, a guanine nucleotide exchange factor for the small cellular GTPases, Arf, is responsible for the sensitivity of virus infection to BFA, and is required for virus replication. Knockdown of GBF1 expression inhibited virus replication, which was rescued by catalytically active protein with an intact N-terminal sequence. We identified a mutation in GBF1 that allows growth of poliovirus in the presence of BFA. Interaction between GBF1 and viral protein 3A determined the outcome of infection in the presence of BFA.
Highlights
All known positive strand RNA viruses replicate their genomes in association with remodeled cellular membranes
Poliovirus replication is severely suppressed by brefeldin A (BFA), a well-known inhibitor of the cellular secretory pathway
Three cellular proteins (GBF1, BIG1 and BIG2) that activate small GTPases called Arfs, whose activity is necessary for normal functioning of the secretory pathway, are known targets of BFA
Summary
All known positive strand RNA viruses replicate their genomes in association with remodeled cellular membranes. Infection of cells with poliovirus results in rapid and massive reorganization of virtually all intracellular membranes except for mitochondria, into clusters of tightly-associated vesicles of heterogeneous size which harbor viral replication complexes on their surfaces [2,3,4]. These replication complexes have been shown to be associated with all of the non-structural viral proteins from the P2 and P3 coding region [5,6]. It was proposed that autophagy-like processes may be involved in membrane remodeling in polio infected cells, which would explain the large proportion of double membrane vesicles observed by electron microscopy of infected cells [9]
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