Induction of GADD34 is necessary for dsRNA-dependent interferon-β production and participates in the control of Chikungunya virus infection

Giovanna Clavarino (1, 2) , Nuno Cláudio (1) , Thérèse Couderc (3) , Alexandre Dalet (1) , Delphine Judith , Voahirana Camosseto (1) , Enrico K Schmidt (1) , Till Wenger (1) , Marc Lecuit (4, 5) , Evelina Gatti (1) , Philippe Pierre (1)

1 CIML - Centre d'Immunologie de Marseille - Luminy
2 LAPM - Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble]
3 Biologie des Infections - Biology of Infection
4 Centre d'infectiologie Necker-Pasteur [CHU Necker]
5 Equipe avenir - Microorganismes et Barrières de l'Hôte

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.

Mots clés: Chikungunya infection; Messenger RNA; Protein synthesis; Immunoblotting; Phosphorylation; Protein translation; Cytokines; Chikungunya virus

Domaines: Microbiologie et Parasitologie

Giovanna Clavarino, Nuno Cláudio, Thérèse Couderc, Alexandre Dalet, Delphine Judith, et al.. Induction of GADD34 is necessary for dsRNA-dependent interferon-β production and participates in the control of Chikungunya virus infection. PLoS Pathogens, 2012, 8 (5), pp.e1002708. ⟨10.1371/journal.ppat.1002708⟩. ⟨hal-00964879⟩