Cellular proteasome activity facilitates herpes simplex virus entry at a postpenetration step.
Herpes simplex virus (HSV) entry into cells is a multistep process that engages the host cell machinery. The proteasome is a large, ATP-dependent, multisubunit protease that plays a critical role in the maintenance of cell homeostasis. A battery of assays were used to demonstrate that proteasome inhibitors blocked an early step in HSV entry that occurred after capsid penetration into the cytosol but prior to capsid arrival at the nuclear periphery. Proteasome-dependent viral entry was not reliant on host or viral protein synthesis. MG132, a peptide aldehyde that competitively inhibits the degradative activity of the proteasome, had a reversible inhibitory effect on HSV entry. HSV can use endocytic or nonendocytic pathways to enter cells. These distinct entry routes were both dependent on proteasome-mediated proteolysis. In addition, HSV successfully entered cells in the absence of a functional host ubiquitin-activating enzyme, suggesting that viral entry is ubiquitin independent. We propose that proteasomal degradation of virion and/or host proteins is required for efficient delivery of incoming HSV capsids to the nucleus.
Delboy
Mark G
MG
Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298-0678, USA.
Roller
Devin G
DG
Nicola
Anthony V
AV
D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D006224:Cricetinae; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D018139:Simplexvirus / Q000502:physiology*; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism; D010948:Viral Plaque Assay; D053586:Virus Internalization; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D061988:Proteasome Inhibitors; D001616:beta-Galactosidase; D046988:Proteasome Endopeptidase Complex; D044764:Ubiquitin-Activating Enzymes; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde