PMID:21262835

Citation	Hastie, KM, Kimberlin, CR, Zandonatti, MA, MacRae, IJ and Saphire, EO (2011) Structure of the Lassa virus nucleoprotein reveals a dsRNA-specific 3' to 5' exonuclease activity essential for immune suppression. Proc. Natl. Acad. Sci. U.S.A. 108:2396-401
Abstract	Lassa fever virus, a member of the family Arenaviridae, is a highly endemic category A pathogen that causes 300,000-500,000 infections per year in Western Africa. The arenaviral nucleoprotein NP has been implicated in suppression of the host innate immune system, but the mechanism by which this occurs has remained elusive. Here we present the crystal structure at 1.5 Å of the immunosuppressive C-terminal portion of Lassa virus NP and illustrate that, unexpectedly, its 3D fold closely mimics that of the DEDDh family of exonucleases. Accompanying biochemical experiments illustrate that NP indeed has a previously unknown, bona fide exonuclease activity, with strict specificity for double-stranded RNA substrates. We further demonstrate that this exonuclease activity is essential for the ability of NP to suppress translocation of IFN regulatory factor 3 and block activation of the innate immune system. Thus, the nucleoprotein is a viral exonuclease with anti-immune activity, and this work provides a unique opportunity to combat arenaviral infections.
Links	PubMed PMC3038715 Online version:10.1073/pnas.1016404108
Keywords	Cell Line; Crystallography, X-Ray; Exoribonucleases/chemistry; Exoribonucleases/immunology; Humans; Immunity, Innate; Interferon Regulatory Factor-3/immunology; Lassa virus/enzymology; Lassa virus/immunology; Nucleoproteins/chemistry; Nucleoproteins/immunology; Protein Structure, Tertiary; RNA, Double-Stranded/chemistry; RNA, Double-Stranded/immunology; Viral Proteins/chemistry; Viral Proteins/immunology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
LASSJ:NCAP		GO:0008408: 3'-5' exonuclease activity	ECO:0000315:		F		Fig. 3	complete CACAO 2439
LASSJ:NCAP		GO:0039548: suppression by virus of host IRF3 activity	ECO:0000315:		P		Fig. 5	complete CACAO 2440
LASSJ:NCAP	enables	GO:0008408: 3'-5' exonuclease activity	ECO:0000315: mutant phenotype evidence used in manual assertion		F		Seeded From UniProt	complete
LASSJ:NCAP	involved_in	GO:0030683: evasion or tolerance by virus of host immune response	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
LASSJ:NCAP	involved_in	GO:0039548: suppression by virus of host IRF3 activity	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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