Structures of Arenaviral Nucleoproteins with Triphosphate dsRNA Reveal a Unique Mechanism of Immune Suppression

Xue Jiang, Qinfeng Huang, Wenjian Wang, Haohao Dong, Hinh Ly, Yuying Liang, Changjiang Dong

Research output: Contribution to journalArticlepeer-review

56 Citations (Scopus)

Abstract

A hallmark of severe Lassa fever is the generalized immune suppression, the mechanism of which is poorly understood. Lassa virus (LASV) nucleoprotein (NP) is the only known 3'-5' exoribonuclease that can suppress type I interferon (IFN) production possibly by degrading immune-stimulatory RNAs. How this unique enzymatic activity of LASV NP recognizes and processes RNA substrates is unknown. We provide an atomic view of a catalytically active exoribonuclease domain of LASV NP (LASV NP-C) in the process of degrading a 5' triphosphate double-stranded (ds) RNA substrate, a typical pathogen-associated molecular pattern molecule, to induce type I IFN production. Additionally, we provide for the first time a high-resolution crystal structure of an active exoribonuclease domain of Tacaribe arenavirus (TCRV) NP. Coupled with the in vitro enzymatic and cell-based interferon suppression assays, these structural analyses strongly support a unified model of an exoribonuclease-dependent IFN suppression mechanism shared by all known arenaviruses. New knowledge learned from these studies should aid the development of therapeutics against pathogenic arenaviruses that can infect hundreds of thousands of individuals and kill thousands annually.
Original languageEnglish
Pages (from-to)16949-16959
Number of pages11
JournalThe Journal of Biological Chemistry
Volume288
Issue number23
Early online date24 Apr 2013
DOIs
Publication statusPublished - 7 Jun 2013

Keywords

  • Immunosuppression
  • Nucleic Acid Enzymology
  • Protein Structure
  • Protein-nucleic Acid Interaction
  • Viral Protein
  • 3′-5′ Exoribonuclease
  • Lassa Fever Virus
  • Tacaribe Virus
  • Type I Interferons
  • Immune Evasion

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