Protein phosphatase 1 subunit Ppp1r15a/GADD34 regulates cytokine production in polyinosinic:polycytidylic acid-stimulated dendritic cells.
In response to inflammatory stimulation, dendritic cells (DCs) have a remarkable pattern of differentiation that exhibits specific mechanisms to control the immune response. Here we show that in response to polyriboinosinic:polyribocytidylic acid (pI:C), DCs mount a specific integrated stress response during which the transcription factor ATF4 and the growth arrest and DNA damage-inducible protein 34 (GADD34/Ppp1r15a), a phosphatase 1 (PP1) cofactor, are expressed. In agreement with increased GADD34 levels, an extensive dephosphorylation of the translation initiation factor eIF2α was observed during DC activation. Unexpectedly, although DCs display an unusual resistance to protein synthesis inhibition induced in response to cytosolic dsRNA, GADD34 expression did not have a major impact on protein synthesis. GADD34, however, was shown to be required for normal cytokine production both in vitro and in vivo. These observations have important implications in linking further pathogen detection with the integrated stress response pathways.
Centre d'Immunologie de Marseille-Luminy,  Aix-Marseille University, 13288 Marseille,  France.
Giovanna
G
Clavarino
Nuno
N
Cláudio
Alexandre
A
Dalet
Seigo
S
Terawaki
Thérèse
T
Couderc
Lionel
L
Chasson
Maurizio
M
Ceppi
Enrico K
EK
Schmidt
Till
T
Wenger
Marc
M
Lecuit
Evelina
E
Gatti
Philippe
P
Pierre
D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011070:Poly I-C / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D019892:eIF-2 Kinase / Q000378:metabolism
D016207:Cytokines; D015852:Eukaryotic Initiation Factor-2; D021122:Protein Subunits; D051701:Activating Transcription Factor 4; D016899:Interferon-beta; D019892:eIF-2 Kinase; C513256:Ppp1r15a protein, mouse; D054645:Protein Phosphatase 1; D011070:Poly I-C