title: Dengue Virus Subverts Host Innate Immunity by Targeting Adaptor Protein MAVS.
abstract: Dengue virus (DENV) is the most common mosquito-borne virus infecting humans and is currently a serious global health challenge. To establish infection in its host cells, DENV must subvert the production and/or antiviral effects of interferon (IFN). The aim of this study was to understand the mechanisms by which DENV suppresses IFN production. We determined that DENV NS4A interacts with mitochondrial antiviral signaling protein (MAVS), which was previously found to activate NF-κB and IFN regulatory factor 3 (IRF3), thus inducing type I IFN in the mitochondrion-associated endoplasmic reticulum membranes (MAMs). We further demonstrated that NS4A is associated with the N-terminal CARD-like (CL) domain and the C-terminal transmembrane (TM) domain of MAVS. This association prevented the binding of MAVS to RIG-I, resulting in the repression of RIG-I-induced IRF3 activation and, consequently, the abrogation of IFN production. Collectively, our findings illustrate a new molecular mechanism by which DENV evades the host immune system and suggest new targets for anti-DENV strategies.
  
  
  
  Type I interferon (IFN) constitutes the first line of host defense against invading viruses. To successfully establish infection, dengue virus (DENV) must counteract either the production or the function of IFN. The mechanism by which DENV suppresses IFN production is poorly understood and characterized. In this study, we demonstrate that the DENV NS4A protein plays an important role in suppressing interferon production through binding MAVS and disrupting the RIG-I-MAVS interaction in mitochondrion-associated endoplasmic reticulum membranes (MAMs). Our study reveals that MAVS is a novel host target of NS4A and provides a molecular mechanism for DENV evasion of the host innate immune response. These findings have important implications for understanding the pathogenesis of DENV and may provide new insights into using NS4A as a therapeutic and/or prevention target.
authors.affiliation: School of Public Health, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China.|Guangdong Province Key Laboratory of Functional Molecules in Oceanic Microorganism (Sun Yat-sen University), Bureau of Education, Guangzhou, China.
authors.forename: Zhenjian
authors.initials: Z
authors.lastname: He
authors.affiliation: Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China.|Guangdong Province Key Laboratory of Functional Molecules in Oceanic Microorganism (Sun Yat-sen University), Bureau of Education, Guangzhou, China.|Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China.|Guangdong Province Key Laboratory of Functional Molecules in Oceanic Microorganism (Sun Yat-sen University), Bureau of Education, Guangzhou, China.|Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Weitao
authors.initials: W
authors.lastname: Wen
authors.affiliation: Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China.|Guangdong Province Key Laboratory of Functional Molecules in Oceanic Microorganism (Sun Yat-sen University), Bureau of Education, Guangzhou, China.|Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China.|Guangdong Province Key Laboratory of Functional Molecules in Oceanic Microorganism (Sun Yat-sen University), Bureau of Education, Guangzhou, China.|Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China.|Guangdong Province Key Laboratory of Functional Molecules in Oceanic Microorganism (Sun Yat-sen University), Bureau of Education, Guangzhou, China.|Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jiahui
authors.initials: J
authors.lastname: Chen
authors.affiliation: Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China.|Guangdong Province Key Laboratory of Functional Molecules in Oceanic Microorganism (Sun Yat-sen University), Bureau of Education, Guangzhou, China.|Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Shu
authors.initials: S
authors.lastname: An
authors.affiliation: Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China.|Guangdong Province Key Laboratory of Functional Molecules in Oceanic Microorganism (Sun Yat-sen University), Bureau of Education, Guangzhou, China.|Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Xinhuai
authors.initials: X
authors.lastname: Dong
authors.affiliation: Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China.|Guangdong Province Key Laboratory of Functional Molecules in Oceanic Microorganism (Sun Yat-sen University), Bureau of Education, Guangzhou, China.|Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Cuiji
authors.initials: C
authors.lastname: Lin
authors.affiliation: Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China.|Guangdong Province Key Laboratory of Functional Molecules in Oceanic Microorganism (Sun Yat-sen University), Bureau of Education, Guangzhou, China.|Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jianchen
authors.initials: J
authors.lastname: Yu
authors.affiliation: Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China.|Guangdong Province Key Laboratory of Functional Molecules in Oceanic Microorganism (Sun Yat-sen University), Bureau of Education, Guangzhou, China.|Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jueheng
authors.initials: J
authors.lastname: Wu
authors.affiliation: Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China.|Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China.|Guangdong Province Key Laboratory of Functional Molecules in Oceanic Microorganism (Sun Yat-sen University), Bureau of Education, Guangzhou, China.|Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Junchao
authors.initials: J
authors.lastname: Cai
authors.affiliation: Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China.|Guangdong Province Key Laboratory of Functional Molecules in Oceanic Microorganism (Sun Yat-sen University), Bureau of Education, Guangzhou, China.|Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China limf@mail.sysu.edu.cn.|Guangdong Province Key Laboratory of Functional Molecules in Oceanic Microorganism (Sun Yat-sen University), Bureau of Education, Guangzhou, China.|Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Mengfeng
authors.initials: M
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000998:Antiviral Agents / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D003715:Dengue / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D003716:Dengue Virus / Q000276:immunology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006367:HeLa Cells; D054884:Host-Pathogen Interactions / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000998:Antiviral Agents; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; C505371:MAVS protein, human; D016328:NF-kappa B; C000601110:NS4A protein, Dengue virus; C437968:PLAAT4 protein, human; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D017361:Viral Nonstructural Proteins