TRAF6 Plays a Proviral Role in Tick-Borne Flavivirus Infection through Interaction with the NS3 Protease.
iScience
; 15: 489-501, 2019 May 31.
Article
in En
| MEDLINE
| ID: mdl-31129244
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Type of study:
Prognostic_studies
Language:
En
Journal:
IScience
Year:
2019
Document type:
Article
Affiliation country:
United States