Abstract
Herpes simplex virus 1 (HSV-1) causes a number of clinical manifestations including cold sores, keratitis, meningitis and encephalitis. Although current drugs are available to treat HSV-1 infection, they can cause side effects such as nephrotoxicity. Moreover, owing to the emergence of drug-resistant HSV-1 strains, new anti-HSV-1 compounds are needed. Because many viruses exploit cellular host proteases and encode their own viral proteases for survival, we investigated the inhibitory effects of a panel of protease inhibitors (TLCK, TPCK, E64, bortezomib, or MG132) on HSV-1 replication and several host cell signaling pathways. We found that HSV-1 infection suppressed c-Raf-MEK1/2-ERK1/2-p90RSK signaling in host cells, which facilitated viral replication. The mechanism by which HSV-1 inhibited ERK signaling was mediated through the polyubiquitination and proteasomal degradation of Ras-guanine nucleotide-releasing factor 2 (Ras-GRF2). Importantly, the proteasome inhibitor MG132 inhibited HSV-1 replication by reversing ERK suppression in infected cells, inhibiting lytic genes (ICP5, ICP27 and UL42) expression, and overcoming the downregulation of Ras-GRF2. These results indicate that the suppression of ERK signaling via proteasomal degradation of Ras-GRF2 is necessary for HSV-1 infection and replication. Given that ERK activation by MG132 exhibits anti-HSV-1 activity, these results suggest that the proteasome inhibitor could serve as a novel therapeutic agent against HSV-1 infection.
Highlights
Herpes simplex virus 1 (HSV-1) is a member of the Alphaherpesvirinae subfamily and a human DNA virus that is known to cause a number of clinical manifestations, including cold sores, keratitis, meningitis and encephalitis[1,2]
By a plaque reduction assay, we investigated whether the protease inhibitors, tosyllysine chloromethyl ketone (TLCK), tosylphenylalanyl chloromethyl ketone (TPCK), E64, bortezomib, or MG132 could suppress HSV-1 replication
We demonstrate that the proteasome inhibitor (MG132 and bortezomib) inhibited HSV-1 replication, and MG132 inhibited lytic gene expression, suggesting that MG132 impairs an early step in the replication cycle before lytic gene expression
Summary
Herpes simplex virus 1 (HSV-1) is a member of the Alphaherpesvirinae subfamily and a human DNA virus that is known to cause a number of clinical manifestations, including cold sores, keratitis, meningitis and encephalitis[1,2]. Some IE products function as triggers for transcriptional activation of E genes associated with viral DNA replication. HSV infection alters several signaling pathways, which can be triggered by viral molecules known as pathogen associated molecular patterns (PAMPs). The ERK and AKT signaling pathways are either dysregulated or utilized by tegument proteins or lytic proteins from a number of viruses including HSV, to establish infection, stimulate their replication, and suppress apoptosis[15,16,17,18]. Cellular proteases play a key role in protein degradation and in the regulation of signaling pathways, endocytosis, apoptosis, immune responses, and viral replication. Viruses exploit cellular proteases and encode their own viral proteases for survival, escape from immune responses, replication, assembly, entry and release[25,26]. We investigated the inhibitory effects of several protease inhibitors on HSV replication and elucidated their underlying mechanisms
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