RRC ID 31962
Author Demay Y, Perochon J, Szuplewski S, Mignotte B, Gaumer S.
Title The PERK pathway independently triggers apoptosis and a Rac1/Slpr/JNK/Dilp8 signaling favoring tissue homeostasis in a chronic ER stress Drosophila model.
Journal Cell Death Dis
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.
Volume 5(10)
Pages e1452
Published 2014-10-9
DOI 10.1038/cddis.2014.403
PII cddis2014403
PMID 25299777
PMC PMC4649510
MeSH Animals Apoptosis* Drosophila / cytology Drosophila / genetics Drosophila / metabolism* Drosophila Proteins / genetics Drosophila Proteins / metabolism* Endoplasmic Reticulum Stress* Humans Inhibitor of Apoptosis Proteins / genetics Inhibitor of Apoptosis Proteins / metabolism* Intercellular Signaling Peptides and Proteins / genetics Intercellular Signaling Peptides and Proteins / metabolism* MAP Kinase Kinase 4 / genetics MAP Kinase Kinase 4 / metabolism* MAP Kinase Kinase Kinases / genetics MAP Kinase Kinase Kinases / metabolism* Models, Animal Presenilins / genetics Presenilins / metabolism Signal Transduction Unfolded Protein Response eIF-2 Kinase / genetics eIF-2 Kinase / metabolism* rac GTP-Binding Proteins / genetics rac GTP-Binding Proteins / metabolism*
IF 6.304
Times Cited 21
Drosophila 4353R-2