Viral protein engagement of GBF1 induces host cell vulnerability through synthetic lethality

Area of Science:

• Virology and Molecular Biology
• Drug Discovery and Development

Background:

• Viruses rely on host cell proteins for replication, often repurposing them into functional compromises termed viral-induced hypomorphs.
• Synthetic lethality, a strategy successfully used in cancer therapy, involves targeting synthetic lethal partners of loss-of-function mutations.
• This principle offers a potential avenue for developing host-based antiviral therapeutics by exploiting viral-induced cellular vulnerabilities.

Approach:

• The study used Guanine nucleotide exchange factor BetA (GBF1), essential for many RNA viruses, as a proof-of-concept viral-induced hypomorph.
• GBF1 was shown to become a hypomorph upon interaction with poliovirus protein 3A.
• A screen for GBF1 synthetic lethal partners identified ADP-ribosylation factor 1 (ARF1) as a key interaction.

Key Points:

• Disruption of ARF1 selectively eliminated cells synthesizing poliovirus 3A, demonstrating targeted cell killing.
• This highlights that viral protein interactions can induce hypomorphic states in host cells.
• These induced hypomorphs render infected cells vulnerable to specific perturbations, leaving uninfected cells unharmed.

Conclusions:

• Exploiting these viral-induced vulnerabilities presents a promising strategy for developing broad-spectrum antivirals.
• This approach could be applicable to a wide range of viruses, including SARS-CoV-2.
• The findings validate synthetic lethality as a mechanism for selectively targeting virus-infected cells.