title: Mutual antagonism between the Ebola virus VP35 protein and the RIG-I activator PACT determines infection outcome.
abstract: The cytoplasmic pattern recognition receptor RIG-I is activated by viral RNA and induces type I IFN responses to control viral replication. The cellular dsRNA binding protein PACT can also activate RIG-I. To counteract innate antiviral responses, some viruses, including Ebola virus (EBOV), encode proteins that antagonize RIG-I signaling. Here, we show that EBOV VP35 inhibits PACT-induced RIG-I ATPase activity in a dose-dependent manner. The interaction of PACT with RIG-I is disrupted by wild-type VP35, but not by VP35 mutants that are unable to bind PACT. In addition, PACT-VP35 interaction impairs the association between VP35 and the viral polymerase, thereby diminishing viral RNA synthesis and modulating EBOV replication. PACT-deficient cells are defective in IFN induction and are insensitive to VP35 function. These data support a model in which the VP35-PACT interaction is mutually antagonistic and plays a fundamental role in determining the outcome of EBOV infection.
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai School, New York, NY 10029, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Luthra
authors.forename: Parameshwaran
authors.initials: P
authors.lastname: Ramanan
authors.forename: Chad E
authors.initials: CE
authors.lastname: Mire
authors.forename: Carla
authors.initials: C
authors.lastname: Weisend
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Tsuda
authors.forename: Benjamin
authors.initials: B
authors.lastname: Yen
authors.forename: Gai
authors.initials: G
authors.lastname: Liu
authors.forename: Daisy W
authors.initials: DW
authors.lastname: Leung
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Geisbert
authors.forename: Hideki
authors.initials: H
authors.lastname: Ebihara
authors.forename: Gaya K
authors.initials: GK
authors.lastname: Amarasinghe
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Basler
mesh_terms: D020816:Amino Acid Motifs; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D029043:Ebolavirus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019142:Hemorrhagic Fever, Ebola / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D006801:Humans; D011485:Protein Binding; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic; D054334:Viral Regulatory and Accessory Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C104647:PRKRA protein, human; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D011971:Receptors, Immunologic; C080980:VP35 protein, filovirus; D054334:Viral Regulatory and Accessory Proteins; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases