Different effect of proteasome inhibition on vesicular stomatitis virus and poliovirus replication.
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 eIF2alpha, 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.
Neznanov
Nickolay
N
Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States of America. neznann@ccf.org
Dragunsky
Eugenia M
EM
Chumakov
Konstantin M
KM
Neznanova
Lubov
L
Wek
Ronald C
RC
Gudkov
Andrei V
AV
Banerjee
Amiya K
AK
D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D004247:DNA / Q000378:metabolism; D004261:DNA Replication; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008954:Models, Biological; D017955:Poliovirus / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology; D014162:Transfection; D018116:Vesiculovirus / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication
D001897:Boronic Acids; D015852:Eukaryotic Initiation Factor-2; D007976:Leupeptins; D061988:Proteasome Inhibitors; D011719:Pyrazines; D014764:Viral Proteins; D000069286:Bortezomib; D004247:DNA; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde