Protein synthesis inhibition and GADD34 control IFN‐β heterogeneous expression in response to dsRNA

Alexandre Dalet (1) , Rafael J Argüello (1) , Alexis Combes (1) , Lionel Spinelli (1) , Sebastien Jaeger (1) , Mathieu Fallet (1) , Thien‐phong Vu Manh (1) , Andreia Mendes (1) , Jessica Perego (1) , Marisa Reverendo (1) , Voahirana Camosseto (1) , Marc Dalod (1) , Tobias Weil (2) , Manuel A Santos (2) , Evelina Gatti (1, 2) , Philippe Pierre (1)

1 CIML - Centre d'Immunologie de Marseille - Luminy
2 iBiMED - Institute for Research in Biomedicine

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 eIF2a 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-b mRNA transcription , while GADD34-dependent protein synthesis recovery contributes to the heterogeneous expression of IFN observed in dsRNA-activated cells.

Mots clés: CGAMP; Integrated stress response; Puromycin; RIG-I-like receptors; Stress granules; Immunology

Domaines: Immunologie; Biologie cellulaire

Alexandre Dalet, Rafael J Argüello, Alexis Combes, Lionel Spinelli, Sebastien Jaeger, et al.. Protein synthesis inhibition and GADD34 control IFN‐β heterogeneous expression in response to dsRNA. EMBO Journal, 2017, 36 (6), pp.761 - 782. ⟨10.15252/embj.201695000⟩. ⟨hal-01476255⟩