In vivo imaging of the spatiotemporal activity of the eIF2α-ATF4 signaling pathway: Insights into stress and related disorders.
The eIF2α-ATF4 pathway is involved in cellular adaptation to stress and is dysregulated in numerous diseases. Activation of this pathway leads to phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α) and the recruitment of the transcription factor ATF4 (activating transcription factor 4) to specific CCAAT/enhancer binding protein (C/EBP)-ATF response elements (CAREs) located in the promoters of target genes. To monitor the spatiotemporal modulation of this pathway in living animals, we generated a novel CARE-driven luciferase mouse model (CARE-LUC). These transgenic mice enable the investigation of the eIF2α-ATF4 pathway activity in the whole organism and at the tissue and cellular levels by combining imaging, luciferase assays, and immunochemistry. Using this mouse line, we showed the tissue-specific activation pattern of this pathway in response to amino acid deficiency or endoplasmic reticulum stress and the hepatic induction of this pathway in a stress-related pathology model of liver fibrosis. The CARE-LUC mouse model represents an innovative tool to investigate the eIF2α-ATF4 axis and to develop drugs targeting this important pathway in the remediation of related pathologies.
Institut National de la Recherche Agronomique (INRA), UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, 63122 Saint Genès Champanelle, France. Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, 63000 Clermont-Ferrand, France.
Cédric
C
Chaveroux
Institut National de la Recherche Agronomique (INRA), UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, 63122 Saint Genès Champanelle, France. Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, 63000 Clermont-Ferrand, France.
Valérie
V
Carraro
Institut de Génomique Fonctionnelle de Lyon, IGFL UMR 5242 CNRS, ENS Lyon, INRA 1288, UCBL, 69364 Lyon, France.
Laurence
L
Canaple
Institut National de la Recherche Agronomique (INRA), UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, 63122 Saint Genès Champanelle, France. Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, 63000 Clermont-Ferrand, France.
Julien
J
Averous
Institut National de la Recherche Agronomique (INRA), UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, 63122 Saint Genès Champanelle, France. Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, 63000 Clermont-Ferrand, France.
Anne-Catherine
AC
Maurin
Institut National de la Recherche Agronomique (INRA), UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, 63122 Saint Genès Champanelle, France. Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, 63000 Clermont-Ferrand, France.
Céline
C
Jousse
Institut National de la Recherche Agronomique (INRA), UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, 63122 Saint Genès Champanelle, France. Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, 63000 Clermont-Ferrand, France.
Yuki
Y
Muranishi
Institut National de la Recherche Agronomique (INRA), UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, 63122 Saint Genès Champanelle, France. Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, 63000 Clermont-Ferrand, France.
Laurent
L
Parry
Institut National de la Recherche Agronomique (INRA), UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, 63122 Saint Genès Champanelle, France. Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, 63000 Clermont-Ferrand, France.
Florent
F
Mesclon
Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, U2M, 13288 Marseille, France. INSERM, U1104, 13288 Marseille, France. CNRS, UMR 7280, 13288 Marseille, France. Institute for Research in Biomedicine (iBiMED) and Aveiro Health Sciences Program University of Aveiro, 3810-193 Aveiro, Portugal.
Evelina
E
Gatti
Institut du Cerveau et de la Moelle Epinière, Biotechnology and Biotherapy Team, Hôpital Pitié Salpêtrière, 47 Bd. De l'Hôpital, 75013 Paris, France.
Jacques
J
Mallet
Institut du Cerveau et de la Moelle Epinière, Biotechnology and Biotherapy Team, Hôpital Pitié Salpêtrière, 47 Bd. De l'Hôpital, 75013 Paris, France.
Philippe
P
Ravassard
Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, U2M, 13288 Marseille, France. INSERM, U1104, 13288 Marseille, France. CNRS, UMR 7280, 13288 Marseille, France. Institute for Research in Biomedicine (iBiMED) and Aveiro Health Sciences Program University of Aveiro, 3810-193 Aveiro, Portugal.
Philippe
P
Pierre
Institut National de la Recherche Agronomique (INRA), UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, 63122 Saint Genès Champanelle, France. Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, 63000 Clermont-Ferrand, France. alain.bruhat@clermont.inra.fr pierre.fafournoux@clermont.inra.fr.
Pierre
P
Fafournoux
Institut National de la Recherche Agronomique (INRA), UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, 63122 Saint Genès Champanelle, France. Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, 63000 Clermont-Ferrand, France. alain.bruhat@clermont.inra.fr pierre.fafournoux@clermont.inra.fr.
Alain
A
Bruhat
D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D057054:Molecular Imaging; D015398:Signal Transduction; D013312:Stress, Physiological
C081452:Atf4 protein, mouse; D015852:Eukaryotic Initiation Factor-2; D051701:Activating Transcription Factor 4