title: Protein synthesis inhibition and GADD34 control IFN-β heterogeneous expression in response to dsRNA.
abstract: In innate immune responses, induction of type-I interferons (IFNs) prevents virus spreading while viral replication is delayed by protein synthesis inhibition. We asked how cells perform these apparently contradictory activities. Using single fibroblast monitoring by flow cytometry and mathematical modeling, we demonstrate that type-I IFN production is linked to cell's ability to enter dsRNA-activated PKR-dependent translational arrest and then overcome this inhibition by decreasing eIF2α phosphorylation through phosphatase 1c cofactor GADD34 (Ppp1r15a) expression. GADD34 expression, shown here to be dependent on the IRF3 transcription factor, is responsible for a biochemical cycle permitting pulse of IFN synthesis to occur in cells undergoing protein synthesis inhibition. Translation arrest is further demonstrated to be key for anti-viral response by acting synergistically with MAVS activation to amplify TBK1 signaling and IFN-β mRNA transcription, while GADD34-dependent protein synthesis recovery contributes to the heterogeneous expression of IFN observed in dsRNA-activated cells.
authors.affiliation: CNRS, INSERM, CIML, Aix Marseille University, Marseille, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Dalet
authors.affiliation: CNRS, INSERM, CIML, Aix Marseille University, Marseille, France.
authors.forename: Rafael J
authors.initials: RJ
authors.lastname: Argüello
authors.affiliation: CNRS, INSERM, CIML, Aix Marseille University, Marseille, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Combes
authors.affiliation: CNRS, INSERM, CIML, Aix Marseille University, Marseille, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Spinelli
authors.affiliation: CNRS, INSERM, CIML, Aix Marseille University, Marseille, France.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Jaeger
authors.affiliation: CNRS, INSERM, CIML, Aix Marseille University, Marseille, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Fallet
authors.affiliation: CNRS, INSERM, CIML, Aix Marseille University, Marseille, France.
authors.forename: Thien-Phong
authors.initials: TP
authors.lastname: Vu Manh
authors.affiliation: CNRS, INSERM, CIML, Aix Marseille University, Marseille, France.
authors.forename: Andreia
authors.initials: A
authors.lastname: Mendes
authors.affiliation: CNRS, INSERM, CIML, Aix Marseille University, Marseille, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Perego
authors.affiliation: CNRS, INSERM, CIML, Aix Marseille University, Marseille, France.
authors.forename: Marisa
authors.initials: M
authors.lastname: Reverendo
authors.affiliation: CNRS, INSERM, CIML, Aix Marseille University, Marseille, France.|International associated laboratory (LIA) CNRS "Mistra", Marseille, France.
authors.forename: Voahirana
authors.initials: V
authors.lastname: Camosseto
authors.affiliation: CNRS, INSERM, CIML, Aix Marseille University, Marseille, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Dalod
authors.affiliation: Institute for Research in Biomedicine - iBiMED and Aveiro Health Sciences Program, University of Aveiro, Aveiro, Portugal.
authors.forename: Tobias
authors.initials: T
authors.lastname: Weil
authors.affiliation: International associated laboratory (LIA) CNRS "Mistra", Marseille, France.|Institute for Research in Biomedicine - iBiMED and Aveiro Health Sciences Program, University of Aveiro, Aveiro, Portugal.
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Santos
authors.affiliation: CNRS, INSERM, CIML, Aix Marseille University, Marseille, France gatti@ciml.univ-mrs.fr pierre@ciml.univ-mrs.fr.|International associated laboratory (LIA) CNRS "Mistra", Marseille, France.|Institute for Research in Biomedicine - iBiMED and Aveiro Health Sciences Program, University of Aveiro, Aveiro, Portugal.
authors.forename: Evelina
authors.initials: E
authors.lastname: Gatti
authors.affiliation: CNRS, INSERM, CIML, Aix Marseille University, Marseille, France gatti@ciml.univ-mrs.fr pierre@ciml.univ-mrs.fr.|International associated laboratory (LIA) CNRS "Mistra", Marseille, France.|Institute for Research in Biomedicine - iBiMED and Aveiro Health Sciences Program, University of Aveiro, Aveiro, Portugal.
authors.forename: Philippe
authors.identifier: 0000-0003-0863-8255
authors.initials: P
authors.lastname: Pierre
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000276:immunology / Q000821:virology; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D016899:Interferon-beta / Q000378:metabolism*; D051379:Mice; D008962:Models, Theoretical; D014176:Protein Biosynthesis; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D012330:RNA, Double-Stranded / Q000276:immunology* / Q000378:metabolism*
chemical_list: D012330:RNA, Double-Stranded; D016899:Interferon-beta; C513256:Ppp1r15a protein, mouse; D054645:Protein Phosphatase 1
keywords: RIG‐I‐like receptors; cGAMP; integrated stress response; puromycin; stress granules