Abstract
Proteasome activity is an important part of viral replication. In this study, we examined the effect of proteasome inhibitors on the replication of vesicular stomatitis virus (VSV) and poliovirus. We found that the proteasome inhibitors significantly suppressed VSV protein synthesis, virus accumulation, and protected infected cells from toxic effect of VSV replication. In contrast, poliovirus replication was delayed, but not diminished in the presence of the proteasome inhibitors MG132 and Bortezomib. We also found that inhibition of proteasomes stimulated stress-related processes, such as accumulation of chaperone hsp70, phosphorylation of eIF2α, and overall inhibition of translation. VSV replication was sensitive to this stress with significant decline in replication process. Poliovirus growth was less sensitive with only delay in replication. Inhibition of proteasome activity suppressed cellular and VSV protein synthesis, but did not reduce poliovirus protein synthesis. Protein kinase GCN2 supported the ability of proteasome inhibitors to attenuate general translation and to suppress VSV replication. We propose that different mechanisms of translational initiation by VSV and poliovirus determine their sensitivity to stress induced by the inhibition of proteasomes. To our knowledge, this is the first study that connects the effect of stress induced by proteasome inhibition with the efficiency of viral infection.
Highlights
Proteasomes are cellular structures responsible for rapid, efficient and strictly regulated process of protein degradation [1]
Reduced virus yield confirmed that MG132 suppressed vesicular stomatitis virus (VSV) replication in HeLa cells at concentrations starting from 2.5 mM (Fig. 1A)
To analyze VSV protein synthesis, HeLa cells were infected with VSV at multiplicity of infection (MOI) = 5 for 4 h and treated with various amounts of MG132 at a time of infection
Summary
Proteasomes are cellular structures responsible for rapid, efficient and strictly regulated process of protein degradation [1]. The ubiquitin/proteasome pathway is the major route for regulated protein degradation in eukaryotic cells [1]. Besides special targets for ubiquitination and proteasome-specific degradation, such as p53, IkBa, STAT [3,4,5,6], proteasomes are responsible for the degradation of unfolded or improperly folded proteins [7,8]. This activity of proteasomes is important for maintaining cellular protein homeostasis [9,10]. Proteasome specific degradation is an important part of replication of several viruses [11,12]. Some viruses developed mechanisms to target cellular proteins, such as p53 and STAT, for proteasome-specific degradation [13,14]. We studied the role of proteasomes in the replication of vesicular stomatitis virus (VSV) and poliovirus
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