The Nonstructural Protein of Guertu Virus Disrupts Host Defenses by Blocking Antiviral Interferon Induction and Action

Min, Yuan-Qin; Chen, Shi; Yao, Ting; Feng, Kuan; Mo, Qiong; Deng, Fei; Wang, Hualin; Ning, Yun‐Jia

doi:10.1021/acsinfecdis.9b00492

Cited by 17 publications

(30 citation statements)

References 46 publications

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“…EGFPfused N or N-arm expression plasmids were constructed using the pEGFP-N1 vector. Expression plasmids for TBK1, SFTSV N or NSs, or HRTV N and the plasmid expressing Renilla luciferase (pRL-TK) were previously described [15,16,18,59]. Expression plasmids for GTV N, SFTSV GP or SFTSV RdRp were similarly constructed by standard molecular biology technique.…”

Section: Plasmids and Transfectionmentioning

confidence: 99%

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Host restriction of emerging high-pathogenic bunyaviruses via MOV10 by targeting viral nucleoprotein and blocking ribonucleoprotein assembly

Deng

et al. 2020

PLoS Pathog

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Bunyavirus ribonucleoprotein (RNP) that is assembled by polymerized nucleoproteins (N) coating a viral RNA and associating with a viral polymerase can be both the RNA synthesis machinery and the structural core of virions. Bunyaviral N and RNP thus could be assailable targets for host antiviral defense; however, it remains unclear which and how host factors target N/RNP to restrict bunyaviral infection. By mass spectrometry and protein-interaction analyses, we here show that host protein MOV10 targets the N proteins encoded by a group of emerging high-pathogenic representatives of bunyaviruses including severe fever with thrombocytopenia syndrome virus (SFTSV), one of the most dangerous pathogens listed by World Health Organization, in RNA-independent manner. MOV10 that was further shown to be induced specifically by SFTSV and related bunyaviruses in turn inhibits the bunyaviral replication in infected cells in series of loss/gain-of-function assays. Moreover, animal infection experiments with MOV10 knockdown corroborated the role of MOV10 in restricting SFTSV infection and pathogenicity in vivo. Minigenome assays and additional functional and mechanistic investigations demonstrate that the anti-bunyavirus activity of MOV10 is likely achieved by direct impact on viral RNP machinery but independent of its helicase activity and the cellular interferon pathway. Indeed, by its N-terminus, MOV10 binds to a protruding N-arm domain of N consisting of only 34 amino acids but proving important for N function and blocks N polymerization, N-RNA binding, and N-polymerase interaction, disabling RNP assembly. This study not only advances the understanding of bunyaviral replication and host restriction mechanisms but also presents novel paradigms for both direct antiviral action of MOV10 and host targeting of viral RNP machinery.

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Section: Plasmids and Transfectionmentioning

confidence: 99%

“…Act.) were then shown by normalization of firefly luciferase activities to Renilla luciferase activities as described previously [15,16,59].…”

Section: Minigenome Assaymentioning

confidence: 99%

Host restriction of emerging high-pathogenic bunyaviruses via MOV10 by targeting viral nucleoprotein and blocking ribonucleoprotein assembly

Deng

et al. 2020

PLoS Pathog

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“…Moreover, by an ambisense strategy, bandavirus S segment also encodes a non-structural protein (NSs) which is involved in the formation of viral inclusion body and plays important roles at the interface of virus-host interactions ( Yu et al, 2011 ; Ning et al, 2014 ). Particularly, previous studies by us and others have suggested that NSs hijacks several critical host signaling proteins including kinases TANK-binding kinase 1 (TBK1)/IκB kinase ε (IKKε) and transcription factors signal transducer and activator of transcription 1 (STAT1)/STAT2 into the viral inclusion body “jail,” thus blocking interferon (IFN) antiviral immune responses ( Yu et al, 2011 ; Ning et al, 2014 , 2015 , 2017 , 2019 ; Santiago et al, 2014 ; Wu et al, 2014 ; Feng et al, 2019 ; Min et al, 2020a , b ).…”

Section: Introductionmentioning

confidence: 99%

Animal Model of Severe Fever With Thrombocytopenia Syndrome Virus Infection

Sun

Min

et al. 2022

Front. Microbiol.

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Severe fever with thrombocytopenia syndrome (SFTS), an emerging life-threatening infectious disease caused by SFTS bunyavirus (SFTSV; genus Bandavirus, family Phenuiviridae, order Bunyavirales), has been a significant medical problem. Currently, there are no licensed vaccines or specific therapeutic agents available and the viral pathogenesis remains largely unclear. Developing appropriate animal models capable of recapitulating SFTSV infection in humans is crucial for both the study of the viral pathogenic processes and the development of treatment and prevention strategies. Here, we review the current progress in animal models for SFTSV infection by summarizing susceptibility of various potential animal models to SFTSV challenge and the clinical manifestations and histopathological changes in these models. Together with exemplification of studies on SFTSV molecular mechanisms, vaccine candidates, and antiviral drugs, in which animal infection models are utilized, the strengths and limitations of the existing SFTSV animal models and some important directions for future research are also discussed. Further exploration and optimization of SFTSV animal models and the corresponding experimental methods will be undoubtedly valuable for elucidating the viral infection and pathogenesis and evaluating vaccines and antiviral therapies.

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“…Currently, little is known about the interactions of these bunyaviruses with their hosts. Interestingly, we recently demonstrated that similar to SFTSV NSs, the NSs proteins of HRTV and GTV can also target the host kinase TBK1 to inhibit RIG-I-and MDA5-mediated antiviral signaling (77,83). This conservative RLR signaling-targeting activity exhibited by the NSs proteins may reflect the general involvement of RLRs in the pathogenesis of these bunyaviruses.…”

Section: Sftsv-host Interactions and Thus Likely Benefiting The Future Development Of Antiviral Therapymentioning

confidence: 99%

A RIG-I–like receptor directs antiviral responses to a bunyavirus and is antagonized by virus-induced blockade of TRIM25-mediated ubiquitination

Min

Ning

Wang

et al. 2020

Journal of Biological Chemistry

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The RIG-I–like receptors (RLRs) retinoic acid–inducible gene I protein (RIG-I) and melanoma differentiation–associated protein 5 (MDA5) are cytosolic pattern recognition receptors that recognize specific viral RNA products and initiate antiviral innate immunity. Severe fever with thrombocytopenia syndrome virus (SFTSV) is a highly pathogenic member of the Bunyavirales. RIG-I, but not MDA5, has been suggested to sense some bunyavirus infections; however, the roles of RLRs in anti-SFTSV immune responses remain unclear. Here, we show that SFTSV infection induces an antiviral response accompanied by significant induction of antiviral and inflammatory cytokines and that RIG-I plays a main role in this induction by recognizing viral 5′-triphosphorylated RNAs and by signaling via the adaptor mitochondrial antiviral signaling protein. Moreover, MDA5 may also sense SFTSV infection and contribute to IFN induction, but to a lesser extent. We further demonstrate that the RLR-mediated anti-SFTSV signaling can be antagonized by SFTSV nonstructural protein (NSs) at the level of RIG-I activation. Protein interaction and MS-based analyses revealed that NSs interacts with the host protein tripartite motif–containing 25 (TRIM25), a critical RIG-I–activating ubiquitin E3 ligase, but not with RIG-I or Riplet, another E3 ligase required for RIG-I ubiquitination. NSs specifically trapped TRIM25 into viral inclusion bodies and inhibited TRIM25-mediated RIG-I-Lys-63–linked ubiquitination/activation, contributing to suppression of RLR-mediated antiviral signaling at its initial stage. These results provide insights into immune responses to SFTSV infection and clarify a mechanism of the viral immune evasion, which may help inform the development of antiviral therapeutics.

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The Nonstructural Protein of Guertu Virus Disrupts Host Defenses by Blocking Antiviral Interferon Induction and Action

Cited by 17 publications

References 46 publications

Host restriction of emerging high-pathogenic bunyaviruses via MOV10 by targeting viral nucleoprotein and blocking ribonucleoprotein assembly

Host restriction of emerging high-pathogenic bunyaviruses via MOV10 by targeting viral nucleoprotein and blocking ribonucleoprotein assembly

Animal Model of Severe Fever With Thrombocytopenia Syndrome Virus Infection

A RIG-I–like receptor directs antiviral responses to a bunyavirus and is antagonized by virus-induced blockade of TRIM25-mediated ubiquitination

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