Interaction of dengue virus nonstructural protein 5 with Daxx modulates RANTES production.
Dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS), caused by dengue virus (DENV) infection, are important public health problems in the tropical and subtropical regions. Abnormal hemostasis and plasma leakage are the main patho-physiological changes in DHF/DSS. A remarkably increased production of cytokines, the so called 'cytokine storm', is observed in the patients with DHF/DSS. A complex interaction between DENV proteins and the host immune response contributes to cytokine production. However, the molecular mechanism(s) by which DENV nonstructural protein 5 (NS5) mediates these responses has not been fully elucidated. In the present study, yeast two-hybrid assay was performed to identify host proteins interacting with DENV NS5 and a death-domain-associate protein (Daxx) was identified. The in vivo relevance of this interaction was suggested by co-immunoprecipitation and nuclear co-localization of these two proteins in HEK293 cells expressing DENV NS5. HEK293 cells expressing DENV NS5-K/A, which were mutated at the nuclear localization sequences (NLS), were created to assess its functional roles in nuclear translocation, Daxx interaction, and cytokine production. In the absence of NLS, DENV NS5 could neither translocate into the nucleus nor interact with Daxx to increase the DHF-associated cytokine, RANTES (CCL5) production. This work demonstrates the interaction between DENV NS5 and Daxx and the role of the interaction on the modulation of RANTES production.
Division of Molecular Medicine, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Sasiprapa
S
Khunchai
Mutita
M
Junking
Aroonroong
A
Suttitheptumrong
Umpa
U
Yasamut
Nunghathai
N
Sawasdee
Janjuree
J
Netsawang
Atthapan
A
Morchang
Prapaipit
P
Chaowalit
Sansanee
S
Noisakran
Pa-Thai
PT
Yenchitsomanus
Thawornchai
T
Limjindaporn
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D018946:Chemokine CCL5 / Q000096:biosynthesis*; D056970:Co-Repressor Proteins; D003716:Dengue Virus; D057809:HEK293 Cells; D006801:Humans; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000378:metabolism*; D019595:Severe Dengue / Q000276:immunology*; D020798:Two-Hybrid System Techniques; D017361:Viral Nonstructural Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D018946:Chemokine CCL5; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D018832:Molecular Chaperones; C096041:NS5 protein, flavivirus; D009687:Nuclear Proteins; D017361:Viral Nonstructural Proteins