TY - JOUR
T1 - Structures of arenaviral nucleoproteins with triphosphate dsRNA reveal a unique mechanism of immune suppression
AU - Jiang, Xue
AU - Huang, Qinfeng
AU - Wang, Wenjian
AU - Dong, Haohao
AU - Ly, Hinh
AU - Liang, Yuying
AU - Dong, Changjiang
PY - 2013/6/7
Y1 - 2013/6/7
N2 - 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. Newknowledge 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.
AB - 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. Newknowledge 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.
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U2 - 10.1074/jbc.M112.420521
DO - 10.1074/jbc.M112.420521
M3 - Article
C2 - 23615902
AN - SCOPUS:84878760993
SN - 0021-9258
VL - 288
SP - 16949
EP - 16959
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 23
ER -