title: Activation of Nrf2 by the dengue virus causes an increase in CLEC5A, which enhances TNF-α production by mononuclear phagocytes.
abstract: Infection by the dengue virus (DENV) threatens global public health due to its high prevalence and the lack of effective treatments. Host factors may contribute to the pathogenesis of DENV; herein, we investigated the role of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which is activated by DENV in mononuclear phagocytes. DENV infection selectively activates Nrf2 following nuclear translocation. Following endoplasmic reticular (ER) stress, protein kinase R-like ER kinase (PERK) facilitated Nrf2-mediated transcriptional activation of C-type lectin domain family 5, member A (CLEC5A) to increase CLEC5A expression. Signaling downstream of the Nrf2-CLEC5A interaction enhances Toll-like receptor 3 (TLR3)-independent tumor necrosis factor (TNF)-α production following DENV infection. Forced expression of the NS2B3 viral protein induces Nrf2 nuclear translocation/activation and CLEC5A expression which increases DENV-induced TNF-α production. Animal studies confirmed Nrf2-induced CLEC5A and TNF-α in brains of DENV-infected mice. These results demonstrate that DENV infection causes Nrf2-regulated TNF-α production by increasing levels of CLEC5A.
authors: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.|Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 701, Taiwan.
authors: Yi-Lin
authors: YL
authors: Cheng
authors: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.|Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 701, Taiwan.|Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
authors: Yee-Shin
authors: YS
authors: Lin
authors: Translational Research Center, Taipei Medical University, Taipei 110, Taiwan.
authors: Chia-Ling
authors: CL
authors: Chen
authors: Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
authors: Tsung-Ting
authors: TT
authors: Tsai
authors: Department of Nursing, Chung Hwa University of Medical Technology, Tainan 717, Taiwan.
authors: Cheng-Chieh
authors: CC
authors: Tsai
authors: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.|Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 701, Taiwan.
authors: Yan-Wei
authors: YW
authors: Wu
authors: Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
authors: Yi-Dan
authors: YD
authors: Ou
authors: Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan 701, Taiwan.
authors: Yu-Yi
authors: YY
authors: Chu
authors: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.|Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 701, Taiwan.|Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan 701, Taiwan.
authors: Ju-Ming
authors: JM
authors: Wang
authors: Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
authors: Chia-Yi
authors: CY
authors: Yu
authors: Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 701, Taiwan.|Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.|Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
authors: Chiou-Feng
authors: CF
authors: Lin
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D006224:Cricetinae; D003716:Dengue Virus / Q000502:physiology*; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000378:metabolism / Q000821:virology*; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C509771:CLEC5A protein, human; C509772:Clec5a protein, mouse; D037181:Lectins, C-Type; D051267:NF-E2-Related Factor 2; D011956:Receptors, Cell Surface; D051196:Toll-Like Receptor 3; D014409:Tumor Necrosis Factor-alpha; D017361:Viral Nonstructural Proteins