The C-Terminal Region Of Lymphocytic Choriomeningitis Virus Nucleoprotein Contains Distinct And Segregable Functional Domains Involved In NP-Z Interaction And Counteraction Of The Type I IFN Response

Several arenaviruses cause hemorrhagic fever (HF) disease in humans that is associated with high morbidity and significant mortality. Arenavirus nucleoprotein (NP), the most abundant viral protein in infected cells and virions, encapsidates the viral genome RNA, and this NP-RNA complex together with the viral L polymerase form the viral ribonucleoprotein (vRNP) that directs viral RNA replication and gene transcription. Formation of infectious arenavirus progeny requires packaging of vRNPs into budding particles, a process in which arenavirus matrix-like protein (Z) plays a central role. In the present study we have characterized the NP-Z interaction for the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV). The LCMV-NP domain that interacted with Z overlapped with a previously documented C-terminal domain that counteracts the host type I IFN response. However, we found that single amino acid mutations that affect the anti-IFN function of LCMV-NP did not disrupt the NP-Z interaction, suggesting that within the C-terminal region of NP different amino acid residues critically contribute to these two distinct and segregable NP functions. A similar NP-Z interaction was confirmed for the HF arenavirus Lassa virus (LASV). Notably, LCMV-NP interacted similarly with both, LCMVand LASV-Z, while LASV-NP interacted only with LASV-Z. Our results also suggest the presence of a conserved protein domain within NP but with specific amino acid residues playing key roles in determining the specificity of NP-Z interaction that may influence the viability of reassortant arenaviruses. In addition, this NP-Z interaction represents a potential target for the development of antiviral drugs to combat human pathogenic arenaviruses. on D ecem er 5, 2017 by gest http/jvi.asm .rg/ D ow nladed fom