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
Affiliations
Brian H. Youseff
Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
Thomas G. Brewer
Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
Kristin L. McNally
Innate Immunity and Pathogenesis Unit, Laboratory of Virology, Rocky Mountain Laboratories, DIR, NIAID, NIH, Hamilton, MT 59840, USA
Adaeze O. Izuogu
Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
Kirk J. Lubick
Innate Immunity and Pathogenesis Unit, Laboratory of Virology, Rocky Mountain Laboratories, DIR, NIAID, NIH, Hamilton, MT 59840, USA
John B. Presloid
Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
Saad Alqahtani
Department of Chemistry and Biochemistry, University of Toledo, Toledo, OH 43606, USA
Saurabh Chattopadhyay
Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
Sonja M. Best
Innate Immunity and Pathogenesis Unit, Laboratory of Virology, Rocky Mountain Laboratories, DIR, NIAID, NIH, Hamilton, MT 59840, USA
Xiche Hu
Department of Chemistry and Biochemistry, University of Toledo, Toledo, OH 43606, USA
R. Travis Taylor
Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; Corresponding author
Summary: 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. : Molecular Interaction; Microbiology; Viral Microbiology Subject Areas: Molecular Interaction, Microbiology, Viral Microbiology
