title: The PERK pathway independently triggers apoptosis and a Rac1/Slpr/JNK/Dilp8 signaling favoring tissue homeostasis in a chronic ER stress Drosophila model.
abstract: The endoplasmic reticulum (ER) has a major role in protein folding. The accumulation of unfolded proteins in the ER induces a stress, which can be resolved by the unfolded protein response (UPR). Chronicity of ER stress leads to UPR-induced apoptosis and in turn to an unbalance of tissue homeostasis. Although ER stress-dependent apoptosis is observed in a great number of devastating human diseases, how cells activate apoptosis and promote tissue homeostasis after chronic ER stress remains poorly understood. Here, using the Drosophila wing imaginal disc as a model system, we validated that Presenilin overexpression induces chronic ER stress in vivo. We observed, in this novel model of chronic ER-stress, a PERK/ATF4-dependent apoptosis requiring downregulation of the antiapoptotic diap1 gene. PERK/ATF4 also activated the JNK pathway through Rac1 and Slpr activation in apoptotic cells, leading to the expression of Dilp8. This insulin-like peptide caused a developmental delay, which partially allowed the replacement of apoptotic cells. Thanks to a novel chronic ER stress model, these results establish a new pathway that both participates in tissue homeostasis and triggers apoptosis through an original regulation.
authors.affiliation: Laboratoire de Génétique et Biologie Cellulaire, EA4589, Université Versailles-St-Quentin-en-Yvelines, Ecole Pratique des Hautes Etudes, 2 avenue de la Source de la Bièvre, Montigny-le-Bretonneux, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Demay
authors.affiliation: Laboratoire de Génétique et Biologie Cellulaire, EA4589, Université Versailles-St-Quentin-en-Yvelines, Ecole Pratique des Hautes Etudes, 2 avenue de la Source de la Bièvre, Montigny-le-Bretonneux, France.
authors.forename: J
authors.initials: J
authors.lastname: Perochon
authors.affiliation: Laboratoire de Génétique et Biologie Cellulaire, EA4589, Université Versailles-St-Quentin-en-Yvelines, Ecole Pratique des Hautes Etudes, 2 avenue de la Source de la Bièvre, Montigny-le-Bretonneux, France.
authors.forename: S
authors.initials: S
authors.lastname: Szuplewski
authors.affiliation: Laboratoire de Génétique et Biologie Cellulaire, EA4589, Université Versailles-St-Quentin-en-Yvelines, Ecole Pratique des Hautes Etudes, 2 avenue de la Source de la Bièvre, Montigny-le-Bretonneux, France.
authors.forename: B
authors.initials: B
authors.lastname: Mignotte
authors.affiliation: Laboratoire de Génétique et Biologie Cellulaire, EA4589, Université Versailles-St-Quentin-en-Yvelines, Ecole Pratique des Hautes Etudes, 2 avenue de la Source de la Bièvre, Montigny-le-Bretonneux, France.
authors.forename: S
authors.initials: S
authors.lastname: Gaumer
mesh_terms: D000818:Animals; D017209:Apoptosis; D004330:Drosophila / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D023421:Models, Animal; D053763:Presenilins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D051034:Inhibitor of Apoptosis Proteins; D036341:Intercellular Signaling Peptides and Proteins; D048670:MAP Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases; D053763:Presenilins; D019892:eIF-2 Kinase; D020744:rac GTP-Binding Proteins; C111891:DIAP1 protein, Drosophila; C090146:Rac1 protein, Drosophila; C572149:insulin-like peptide 8, Drosophila; C447860:slpr protein, Drosophila