Proximity interactome analysis of Lassa polymerase reveals eRF3a/GSPT1 as a druggable target for host-directed antivirals

A Lassa virus (LASV) RNA-dependent RNA-polymerase-biotin ligase (TurboID) fusion protein that retained polymerase activity successfully biotinylates the proximal proteome. By using a minigenome assay performed by this LASV polymerase, 42 host proteins were defined as LASV polymerase interactors. A small interfering RNA screen has been also performed to examine whether these interactors have functional roles in authentic LASV infection. As the result, an eukaryotic peptide chain release factor subunit 3a (eRF3a/GSPT1) was identified to be a pivotal factor that physically associates with LASV polymerase. The degradation of GSPT1 by a small-molecule drug resulted in the strong inhibition of LASV infection, showing that this inhibition could be an attractive target for antivirals.