Viral protein engagement of GBF1 induces host cell vulnerability through synthetic lethality
Gene Expression Regulation, Viral
0301 basic medicine
0303 health sciences
Viral Core Proteins
Virus Replication
Article
3. Good health
Poliovirus
03 medical and health sciences
Report
Host-Pathogen Interactions
Humans
Guanine Nucleotide Exchange Factors
Synthetic Lethal Mutations
DOI:
10.1083/jcb.202011050
Publication Date:
2022-10-28T13:02:12Z
AUTHORS (10)
ABSTRACT
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.
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