TRAF6 Plays a Proviral Role in Tick-Borne Flavivirus Infection through Interaction with the NS3 Protease
| Autor: | Thomas G. Brewer, Kirk J. Lubick, Adaeze O. Izuogu, Saurabh Chattopadhyay, Saad Alqahtani, Kristin L. McNally, John B. Presloid, Sonja M. Best, Xiche Hu, Brian H. Youseff, R. Travis Taylor |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment In silico viruses 02 engineering and technology Biology medicine.disease_cause Microbiology Article Virus 03 medical and health sciences Viral Microbiology medicine lcsh:Science NS3 Mutation Multidisciplinary Innate immune system Protease Molecular Interaction virus diseases biochemical phenomena metabolism and nutrition 021001 nanoscience & nanotechnology Virology 3. Good health 030104 developmental biology Viral replication Tumor necrosis factor alpha lcsh:Q 0210 nano-technology |
| Zdroj: | iScience, Vol 15, Iss, Pp 489-501 (2019) iScience |
| ISSN: | 2589-0042 |
| Popis: | 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. Graphical Abstract Highlights • Langat virus (LGTV) NS3 protease interacts with TRAF6 during infection • Tick-borne, unlike mosquito-borne, flaviviruses use TRAF6 for optimal replication • E117A mutation of LGTV NS3 reduces TRAF6 binding and mature protease abundance • LGTV with a mutated TRAF6-binding motif is attenuated in vitro Molecular Interaction; Microbiology; Viral Microbiology |
| Databáze: | OpenAIRE |
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