The ubiquitin proteasome system plays a role in venezuelan equine encephalitis virus infection.
Authors: Amaya Moushimi, Keck Forrest, Lindquist Michael, Voss Kelsey, Scavone Lauren, Kehn-Hall Kylene, Roberts Brian, Bailey Charles, Schmaljohn Connie, Narayanan Aarthi
Journal: PloS one
Summary
Venezuelan equine encephalitis virus (VEEV) exploits the host cell's ubiquitin proteasome system—the cellular machinery responsible for protein degradation and regulation—to replicate effectively, presenting a potential therapeutic vulnerability that researchers investigated using bortezomib, an FDA-approved proteasome inhibitor already in clinical use for cancer treatment. In human astrocytoma cells, bortezomib potently suppressed multiplication of both virulent and attenuated VEEV strains, and notably demonstrated broad-spectrum activity against other New World alphaviruses (Eastern and Western equine encephalitis viruses), with viral inhibition occurring even when the drug was administered several hours after initial viral exposure. Mechanistic investigation revealed that the viral capsid protein undergoes ubiquitination at lysine 48 (K48) residues during early infection stages, a process disrupted by proteasome inhibition, suggesting this modification is critical to the virus's replication cycle. Because no approved vaccines or therapeutics currently exist for VEEV infections and equine encephalitis viruses pose significant biosecurity concerns, these findings identify the ubiquitin proteasome system as a viable target for developing broad-spectrum antiviral therapies—potentially repurposing existing drugs rather than requiring entirely novel compounds. Whilst further work is needed to establish efficacy in vivo and assess safety profiles in equine patients, this research offers a rational foundation for investigating host-directed therapeutic strategies against alphavirus infections in horses.
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Practical Takeaways
- •This is basic research on viral mechanisms in cell culture with no direct clinical application to equine patients at this stage
- •Findings may eventually inform development of novel antivirals for alphavirus infections in horses, but therapeutic translation is not yet established
- •Current relevance to equine practitioners is primarily in understanding that proteasome inhibition is a potential therapeutic strategy under investigation for these serious viral diseases
Key Findings
- •Bortezomib, a proteasome inhibitor, potently inhibited VEEV multiplication in human astrocytoma cells at non-toxic concentrations
- •Bortezomib demonstrated broad-spectrum activity against New World alphaviruses including virulent and attenuated VEEV strains, EEEV, and WEEV
- •The VEEV capsid protein is ubiquitinated on K48 residues during early infection stages, and this ubiquitination is disrupted by Bortezomib treatment
- •Bortezomib effectively inhibited viral multiplication even when administered many hours post-viral exposure