title: Dengue Virus Perturbs Mitochondrial Morphodynamics to Dampen Innate Immune Responses.
abstract: With no antiviral drugs or widely available vaccines, Dengue virus (DENV) constitutes a public health concern. DENV replicates at ER-derived cytoplasmic structures that include substructures called convoluted membranes (CMs); however, the purpose of these membrane alterations remains unclear. We determine that DENV nonstructural protein (NS)4B, a promising drug target with unknown function, associates with mitochondrial proteins and alters mitochondria morphology to promote infection. During infection, NS4B induces elongation of mitochondria, which physically contact CMs. This restructuring compromises the integrity of mitochondria-associated membranes, sites of ER-mitochondria interface critical for innate immune signaling. The spatio-temporal parameters of CM biogenesis and mitochondria elongation are linked to loss of activation of the fission factor Dynamin-Related Protein-1. Mitochondria elongation promotes DENV replication and alleviates RIG-I-dependent activation of interferon responses. As Zika virus infection induces similar mitochondria elongation, this perturbation may protect DENV and related viruses from innate immunity and create a favorable replicative environment.
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany. Electronic address: laurent.chatel-chaix@iaf.inrs.ca.
authors.forename: Laurent
authors.initials: L
authors.lastname: Chatel-Chaix
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Cortese
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany; German Centre for Infection Research, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Inés
authors.initials: I
authors.lastname: Romero-Brey
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Bender
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.
authors.forename: Christopher John
authors.initials: CJ
authors.lastname: Neufeldt
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Fischl
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.
authors.forename: Pietro
authors.initials: P
authors.lastname: Scaturro
authors.affiliation: European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schieber
authors.affiliation: European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Schwab
authors.affiliation: Computational Genome Biology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Fischer
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.
authors.forename: Alessia
authors.initials: A
authors.lastname: Ruggieri
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany; German Centre for Infection Research, Heidelberg University, 69120 Heidelberg, Germany. Electronic address: ralf.bartenschlager@med.uni-heidelberg.de.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bartenschlager
mesh_terms: D003716:Dengue Virus / Q000472:pathogenicity*; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors*; D054884:Host-Pathogen Interactions; D057131:Immune Evasion; D007113:Immunity, Innate; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors*; D008928:Mitochondria / Q000648:ultrastructure*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors*; D017361:Viral Nonstructural Proteins / Q000378:metabolism*
chemical_list: D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; C080107:NS4B protein, flavivirus; D017361:Viral Nonstructural Proteins; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins