title: Induction of GADD34 is necessary for dsRNA-dependent interferon-β production and participates in the control of Chikungunya virus infection.
abstract: Nucleic acid sensing by cells is a key feature of antiviral responses, which generally result in type-I Interferon production and tissue protection. However, detection of double-stranded RNAs in virus-infected cells promotes two concomitant and apparently conflicting events. The dsRNA-dependent protein kinase (PKR) phosphorylates translation initiation factor 2-alpha (eIF2α) and inhibits protein synthesis, whereas cytosolic DExD/H box RNA helicases induce expression of type I-IFN and other cytokines. We demonstrate that the phosphatase-1 cofactor, growth arrest and DNA damage-inducible protein 34 (GADD34/Ppp1r15a), an important component of the unfolded protein response (UPR), is absolutely required for type I-IFN and IL-6 production by mouse embryonic fibroblasts (MEFs) in response to dsRNA. GADD34 expression in MEFs is dependent on PKR activation, linking cytosolic microbial sensing with the ATF4 branch of the UPR. The importance of this link for anti-viral immunity is underlined by the extreme susceptibility of GADD34-deficient fibroblasts and neonate mice to Chikungunya virus infection.
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, UM2, Aix-Marseille Université, Marseille, France.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Clavarino
authors.forename: Nuno
authors.initials: N
authors.lastname: Cláudio
authors.forename: Thérèse
authors.initials: T
authors.lastname: Couderc
authors.forename: Alexandre
authors.initials: A
authors.lastname: Dalet
authors.forename: Delphine
authors.initials: D
authors.lastname: Judith
authors.forename: Voahirana
authors.initials: V
authors.lastname: Camosseto
authors.forename: Enrico K
authors.initials: EK
authors.lastname: Schmidt
authors.forename: Till
authors.initials: T
authors.lastname: Wenger
authors.forename: Marc
authors.initials: M
authors.lastname: Lecuit
authors.forename: Evelina
authors.initials: E
authors.lastname: Gatti
authors.forename: Philippe
authors.initials: P
authors.lastname: Pierre
mesh_terms: D016475:3T3 Cells; D051701:Activating Transcription Factor 4 / Q000378:metabolism; D018354:Alphavirus Infections / Q000276:immunology*; D000818:Animals; D002460:Cell Line; D065632:Chikungunya Fever; D002646:Chikungunya virus / Q000276:immunology*; D005347:Fibroblasts / Q000276:immunology / Q000821:virology; D007370:Interferon Type I / Q000096:biosynthesis; D016899:Interferon-beta / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000096:biosynthesis; D051379:Mice; D011070:Poly I-C / Q000276:immunology; D054645:Protein Phosphatase 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012330:RNA, Double-Stranded / Q000276:immunology*; D019284:Thapsigargin / Q000276:immunology; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000096:biosynthesis / Q000378:metabolism
chemical_list: C081452:Atf4 protein, mouse; D007370:Interferon Type I; D015850:Interleukin-6; D012330:RNA, Double-Stranded; D051701:Activating Transcription Factor 4; D019284:Thapsigargin; D016899:Interferon-beta; D019892:eIF-2 Kinase; C513256:Ppp1r15a protein, mouse; D054645:Protein Phosphatase 1; D011070:Poly I-C