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Protein synthesis inhibition and GADD34 control IFN‐β heterogeneous expression in response to dsRNA
Author(s) -
Dalet Alexandre,
Argüello Rafael J,
Combes Alexis,
Spinelli Lionel,
Jaeger Sebastien,
Fallet Mathieu,
Vu Manh ThienPhong,
Mendes Andreia,
Perego Jessica,
Reverendo Marisa,
Camosseto Voahirana,
Dalod Marc,
Weil Tobias,
Santos Manuel A,
Gatti Evelina,
Pierre Philippe
Publication year - 2017
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201695000
Subject(s) - biology , rna silencing , protein expression , microbiology and biotechnology , protein biosynthesis , rna , rna interference , biochemistry , gene
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.