Lassa virus NP DEDDh 3'-5' exoribonuclease activity is required for optimal viral RNA replication.

LASV NP contains a DEDDh ExoN motif, through which LASV is capable of degrading virus-derived, immunostimulatory dsRNA to eliminate the danger signal and inhibit interferon response. Intriguingly, the NP ExoN motif is highly conserved among arenavirus family, regardless of pathogenicity and viral capability to suppress host innate immune response. Therefore, arenavirus NP ExoN may have yet-to-be-identified function in virus infection. In this study, we discovered that abrogation of LASV NP ExoN activity impaired viral RNA replication in interferon-deficient cells and enhanced virus sensitivity to mutagenic nucleoside analogue. Our new findings indicate that LASV NP ExoN participates in optimal viral RNA replication and open new directions for future studies. Elucidating the function of LASV NP ExoN may promote our understanding of the basics of LASV replication and inform antiviral and vaccine development.