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

• DOI: 10.1083/jcb.202011050
• Publication Date: 2022-10-28T13:02:12Z
• Authors: Arti T. Navare; Fred D. Mast; Jean Paul Olivier; Thierry Bertomeu; Maxwell L. Neal; Lindsay N. Carpp; Alexis Kaushansky; Jasmin Coulombe-H...; Mike Tyers; John D. Aitchison
• Keywords: Replicon; Viral protein; HEK 293 cells

Viruses co-opt host proteins to carry out their lifecycle. Repurposed may thus become functionally compromised; a situation analogous loss-of-function mutation. We term such as viral-induced hypomorphs. Cells bearing cancer driver mutations have successfully been targeted with drugs perturbing encoded by the synthetic lethal (SL) partners of cancer-specific mutations. Similarly, SL interactions hypomorphs can potentially be host-based antiviral therapeutics. Here, we use GBF1, which supports infection many RNA viruses, proof-of-concept. GBF1 becomes hypomorph upon interaction poliovirus protein 3A. Screening for revealed ARF1 top hit, disruption selectively killed cells that synthesize 3A alone or in context replicon. Thus, viral induce render vulnerable perturbations leave uninfected otherwise unscathed. Exploiting vulnerabilities could lead broad-spectrum antivirals including SARS-CoV-2.