title: Dengue Virus Impairs Mitochondrial Fusion by Cleaving Mitofusins.
abstract: Mitochondria are highly dynamic subcellular organelles participating in many signaling pathways such as antiviral innate immunity and cell death cascades. Here we found that mitochondrial fusion was impaired in dengue virus (DENV) infected cells. Two mitofusins (MFN1 and MFN2), which mediate mitochondrial fusion and participate in the proper function of mitochondria, were cleaved by DENV protease NS2B3. By knockdown and overexpression approaches, these two MFNs showed diverse functions in DENV infection. MFN1 was required for efficient antiviral retinoic acid-inducible gene I-like receptor signaling to suppress DENV replication, while MFN2 participated in maintaining mitochondrial membrane potential (MMP) to attenuate DENV-induced cell death. Cleaving MFN1 and MFN2 by DENV protease suppressed mitochondrial fusion and deteriorated DENV-induced cytopathic effects through subverting interferon production and facilitating MMP disruption. Thus, MFNs participate in host defense against DENV infection by promoting the antiviral response and cell survival, and DENV regulates mitochondrial morphology by cleaving MFNs to manipulate the outcome of infection.
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan.|Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Yu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Jian-Jong
authors.initials: JJ
authors.lastname: Liang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Jin-Kun
authors.initials: JK
authors.lastname: Li
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Lee
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Bi-Lan
authors.initials: BL
authors.lastname: Chang
authors.affiliation: Department of Microbiology and Immunology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chan-I
authors.initials: CI
authors.lastname: Su
authors.affiliation: Department of Microbiology and Immunology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Wei-Jheng
authors.initials: WJ
authors.lastname: Huang
authors.affiliation: Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan.|Department of Microbiology and Immunology, National Cheng Kung University, Tainan, Taiwan.|Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.|China Medical University, Taichung, Taiwan.
authors.forename: Michael M C
authors.initials: MM
authors.lastname: Lai
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.|Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Lin
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003715:Dengue / Q000378:metabolism*; D003716:Dengue Virus / Q000378:metabolism*; D005434:Flow Cytometry; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006790:Host-Parasite Interactions / Q000276:immunology*; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D063154:Mitochondrial Dynamics / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014779:Virus Replication / Q000276:immunology
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C470017:Mfn1 protein, human