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

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

Automated summary

Using a viral-induced hypomorph of GBF1, this study demonstrates that the principle of synthetic lethality can selectively kill virus-infected cells. Viral protein interactions can induce hypomorphs in host cells, making them selectively vulnerable to perturbations.