Identification of Critical Amino Acids within the Nucleoprotein of Tacaribe Virus Important for Anti-interferon Activity

Harmon, Brooke; Kozina, Carol L.; Maar, Dianna; Carpenter, Timothy S.; Branda, Catherine; Negrete, Oscar; Carson, Bryan.

doi:10.1074/jbc.m112.444760

Cited by 21 publications

(28 citation statements)

References 29 publications

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“…As this manuscript was in review, an independent study has been published by Harmon et al (31) to describe the role of TCRV NP in suppressing IFN-β production, which reinforces our finding.…”

supporting

confidence: 89%

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

Jiang

Huang

Wang

et al. 2013

Journal of Biological Chemistry

140

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Background: Arenaviral nucleoproteins play a critical role in innate immune suppression.Results: Structures of Lassa nucleoprotein in complex with triphosphate dsRNA and Tacaribe virus nucleoprotein have been determined.Conclusion: Both Lassa and Tacaribe nucleoproteins can strongly inhibit IFN-β production by degrading immune-stimulatory dsRNA.Significance: A unique immune suppression mode of arenaviral nucleoproteins has been revealed.

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supporting

confidence: 89%

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

Jiang

Huang

Wang

et al. 2013

Journal of Biological Chemistry

140

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“…The RNase function of NPs is required for inhibition of PACT-RIG-I-induced IFN-␤ promoter activation. We and other researchers have shown that NP RNase activity was required for its inhibition of type I IFN production (33)(34)(35)(36)(37)(38)(39)(40). To determine whether the RNase activity of NP was also necessary to inhibit PACT-RIG-I-induced IFN-␤ promoter activities, plasmids carrying either WT LASV NP, LASV NP with a known RNase-defective mutation (D389A) (34,38), the C-terminal RNase-containing LASV NP The experiments that generated data for each of the panels shown were repeated three times.…”

Section: Arenaviral Nucleoproteins Block Pact-augmented Rig-i-inducedmentioning

confidence: 93%

“…Specifically, the EBOV VP35, IAV NS1, HSV-1 Us11, MERS-CoV 4a and nucleocapsid (N), as well as MHV N proteins have been shown to directly abolish the interaction between RIG-I and PACT and, hence, block the ability of PACT to activate RIG-I (24,(26)(27)(28)(29)32). We and other researchers have shown previously that arenaviral nucleoproteins (NPs) can efficiently suppress type I IFN production by degrading immunostimulatory RNAs via their intrinsic 3=-to-5= exoribonuclease activity (33)(34)(35)(36)(37)(38)(39)(40). In the present study, we show that LASV NP effectively blocked the PACT-induced augmentation of RIG-I function and therefore suppressed type I IFN production.…”

mentioning

confidence: 99%

Arenaviral Nucleoproteins Suppress PACT-Induced Augmentation of RIG-I Function To Inhibit Type I Interferon Production

Shao

Huang

et al. 2018

J Virol

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RIG-I is a major cytoplasmic sensor of viral pathogen-associated molecular pattern (PAMP) RNA and induces type I interferon (IFN) production upon viral infection. A double-stranded RNA (dsRNA)-binding protein, PACT, plays an important role in potentiating RIG-I function. We have shown previously that arenaviral nucleoproteins (NPs) suppress type I IFN production via their RNase activity to degrade PAMP RNA. We report here that NPs of arenaviruses block the PACT-induced enhancement of RIG-I function to mediate type I IFN production and that this inhibition is dependent on the RNase function of NPs, which is different from that of a known mechanism of other viral proteins to abolish the interaction between PACT and RIG-I. To understand the biological roles of PACT and RIG-I in authentic arenavirus infection, we analyze growth kinetics of recombinant Pichinde virus (PICV), a prototypical arenavirus, in RIG-I knockout (KO) and PACT KO mouse embryonic fibroblast (MEF) cells. Wild-type (WT) PICV grew at higher titers in both KO MEF lines than in normal MEFs, suggesting the important roles of these cellular proteins in restricting virus replication. PICV carrying the NP RNase catalytically inactive mutation could not grow in normal MEFs but could replicate to some extent in both KO MEF lines. The level of virus growth was inversely correlated with the amount of type I IFNs produced. These results suggest that PACT plays an important role in potentiating RIG-I function to produce type I IFNs in order to restrict arenavirus replication and that viral NP RNase activity is essential for optimal viral replication by suppressing PACT-induced RIG-I activation. We report here a new role of the nucleoproteins of arenaviruses that can block type I IFN production via their specific inhibition of the cellular protein sensors of virus infection (RIG-I and PACT). Our results suggest that PACT plays an important role in potentiating RIG-I function to produce type I IFNs in order to restrict arenavirus replication. This new knowledge can be exploited for the development of novel antiviral treatments and/or vaccines against some arenaviruses that can cause severe and lethal hemorrhagic fever diseases in humans.

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“…It is therefore possible to envision the possibility that such processing removes from the viral dsRNA any PAMP hallmark that would be otherwise recognized by RLRs. The fact that critical residues for dsRNA exoribonuclease-mediated IFN inhibition are highly conserved among the NPs of all arenaviruses strongly suggests that this form of the Mask strategy is widely shared within the family (Harmon et al, 2013;Jiang et al, 2013;Qi et al, 2010).…”

Section: Maskmentioning

confidence: 99%

Strategies of highly pathogenic RNA viruses to block dsRNA detection by RIG-I-like receptors: Hide, mask, hit

Zinzula

Tramontano

2013

Antiviral Research

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Double-stranded RNA (dsRNA) is synthesized during the course of infection by RNA viruses as a byproduct of replication and transcription and acts as a potent trigger of the host innate antiviral response. In the cytoplasm of the infected cell, recognition of the presence of viral dsRNA as a signature of "non-self" nucleic acid is carried out by RIG-I-like receptors (RLRs), a set of dedicated helicases whose activation leads to the production of type I interferon α/β (IFN-α/β). To overcome the innate antiviral response, RNA viruses encode suppressors of IFN-α/β induction, which block RLRs recognition of dsRNA by means of different mechanisms that can be categorized into: (i) dsRNA binding and/or shielding ("hide"), (ii) dsRNA termini processing ("mask") and (iii) direct interaction with components of the RLRs pathway ("hit"). In light of recent functional, biochemical and structural findings, we review the inhibition mechanisms of RLRs recognition of dsRNA displayed by a number of highly pathogenic RNA viruses with different disease phenotypes such as haemorrhagic fever (Ebola, Marburg, Lassa fever, Lujo, Machupo, Junin, Guanarito, Crimean-Congo, Rift Valley fever, dengue), severe respiratory disease (influenza, SARS, Hendra, Hantaan, Sin Nombre, Andes) and encephalitis (Nipah, West Nile).

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Identification of Critical Amino Acids within the Nucleoprotein of Tacaribe Virus Important for Anti-interferon Activity

Cited by 21 publications

References 29 publications

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

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

Arenaviral Nucleoproteins Suppress PACT-Induced Augmentation of RIG-I Function To Inhibit Type I Interferon Production

Strategies of highly pathogenic RNA viruses to block dsRNA detection by RIG-I-like receptors: Hide, mask, hit

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