TRAF6 Plays a Proviral Role in Tick-Borne Flavivirus Infection through Interaction with the NS3 Protease

Brian H. Youseff; Thomas G. Brewer; Kristin L. McNally; Adaeze O. Izuogu; Kirk J. Lubick; John B. Presloid; Saad Alqahtani; Saurabh Chattopadhyay; Sonja M. Best; Xiche Hu; R. Travis Taylor

doi:10.1016/j.isci.2019.05.010

TRAF6 Plays a Proviral Role in Tick-Borne Flavivirus Infection through Interaction with the NS3 Protease

Brian H. Youseff, Thomas G. Brewer, Kristin L. McNally, Adaeze O. Izuogu, Kirk J. Lubick, John B. Presloid, Saad Alqahtani, Saurabh Chattopadhyay, Sonja M. Best, Xiche Hu, R. Travis Taylor

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Tick-borne flaviviruses (TBFVs) can cause life-threatening encephalitis and hemorrhagic fever. To identify virus-host interactions that may be exploited as therapeutic targets, we analyzed the TBFV polyprotein in silico for antiviral protein-binding motifs. We obtained two putative tumor necrosis factor receptor-associated factor 6 (TRAF6)-binding motifs (TBMs) within the protease domain of the viral nonstructural 3 (NS3) protein. Here, we show that TBFV NS3 interacted with TRAF6 during infection and that TRAF6 supports TBFV replication. The proviral role of TRAF6 was not seen with mosquito-borne flaviviruses, consistent with the lack of conserved TBMs. Mutation of the second TBM within NS3 disrupted TRAF6 binding, coincident with reduced abundance of mature, autocatalytically derived form of the NS3 protease and significant virus attenuation in vitro. Our studies reveal insights into how flaviviruses exploit innate immunity for the purpose of viral replication and identify a potential target for therapeutic design.

Original language	English
Pages (from-to)	489-501
Number of pages	13
Journal	iScience
Volume	15
DOIs	https://doi.org/10.1016/j.isci.2019.05.010
State	Published - May 31 2019

Bibliographical note

Publisher Copyright:
© 2019 The Author(s)

Funding

We thank Drs. Malathi Krishnamurthy, R. Mark Wooten, and Stanislaw Stepkowski for their guidance and intellectual contributions in helping shape the overarching direction of research. We also thank Dr. Jyl S. Matson for the use of her plate reader and Dr. Alexander G. Pletnev for providing the LGTV infectious clone. We are pleased to acknowledge the Ohio Supercomputer Center for a generous allocation of supercomputer time. This work was supported in part by the Intramural Research Program of the National Institutes of Health and National Institute of Allergy and Infectious Diseases : ZIA-AI001125 to S.M.B. and 1K22-AI099020 to R.T.T.

Funders	Funder number
National Institutes of Health (NIH)
National Institute of Allergy and Infectious Diseases	ZIA-AI001125, 1K22-AI099020

Keywords

Microbiology
Molecular Interaction
Viral Microbiology

ASJC Scopus subject areas

General

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10.1016/j.isci.2019.05.010

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title = "TRAF6 Plays a Proviral Role in Tick-Borne Flavivirus Infection through Interaction with the NS3 Protease",

abstract = "Tick-borne flaviviruses (TBFVs) can cause life-threatening encephalitis and hemorrhagic fever. To identify virus-host interactions that may be exploited as therapeutic targets, we analyzed the TBFV polyprotein in silico for antiviral protein-binding motifs. We obtained two putative tumor necrosis factor receptor-associated factor 6 (TRAF6)-binding motifs (TBMs) within the protease domain of the viral nonstructural 3 (NS3) protein. Here, we show that TBFV NS3 interacted with TRAF6 during infection and that TRAF6 supports TBFV replication. The proviral role of TRAF6 was not seen with mosquito-borne flaviviruses, consistent with the lack of conserved TBMs. Mutation of the second TBM within NS3 disrupted TRAF6 binding, coincident with reduced abundance of mature, autocatalytically derived form of the NS3 protease and significant virus attenuation in vitro. Our studies reveal insights into how flaviviruses exploit innate immunity for the purpose of viral replication and identify a potential target for therapeutic design.",

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note = "Publisher Copyright: {\textcopyright} 2019 The Author(s)",

year = "2019",

month = may,

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doi = "10.1016/j.isci.2019.05.010",

language = "English",

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AU - McNally, Kristin L.

AU - Izuogu, Adaeze O.

AU - Lubick, Kirk J.

AU - Presloid, John B.

AU - Alqahtani, Saad

AU - Chattopadhyay, Saurabh

AU - Best, Sonja M.

AU - Hu, Xiche

AU - Taylor, R. Travis

PY - 2019/5/31

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N2 - Tick-borne flaviviruses (TBFVs) can cause life-threatening encephalitis and hemorrhagic fever. To identify virus-host interactions that may be exploited as therapeutic targets, we analyzed the TBFV polyprotein in silico for antiviral protein-binding motifs. We obtained two putative tumor necrosis factor receptor-associated factor 6 (TRAF6)-binding motifs (TBMs) within the protease domain of the viral nonstructural 3 (NS3) protein. Here, we show that TBFV NS3 interacted with TRAF6 during infection and that TRAF6 supports TBFV replication. The proviral role of TRAF6 was not seen with mosquito-borne flaviviruses, consistent with the lack of conserved TBMs. Mutation of the second TBM within NS3 disrupted TRAF6 binding, coincident with reduced abundance of mature, autocatalytically derived form of the NS3 protease and significant virus attenuation in vitro. Our studies reveal insights into how flaviviruses exploit innate immunity for the purpose of viral replication and identify a potential target for therapeutic design.

AB - Tick-borne flaviviruses (TBFVs) can cause life-threatening encephalitis and hemorrhagic fever. To identify virus-host interactions that may be exploited as therapeutic targets, we analyzed the TBFV polyprotein in silico for antiviral protein-binding motifs. We obtained two putative tumor necrosis factor receptor-associated factor 6 (TRAF6)-binding motifs (TBMs) within the protease domain of the viral nonstructural 3 (NS3) protein. Here, we show that TBFV NS3 interacted with TRAF6 during infection and that TRAF6 supports TBFV replication. The proviral role of TRAF6 was not seen with mosquito-borne flaviviruses, consistent with the lack of conserved TBMs. Mutation of the second TBM within NS3 disrupted TRAF6 binding, coincident with reduced abundance of mature, autocatalytically derived form of the NS3 protease and significant virus attenuation in vitro. Our studies reveal insights into how flaviviruses exploit innate immunity for the purpose of viral replication and identify a potential target for therapeutic design.

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TRAF6 Plays a Proviral Role in Tick-Borne Flavivirus Infection through Interaction with the NS3 Protease

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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