title: ATF3 acts as a rheostat to control JNK signalling during intestinal regeneration.
abstract: Epithelial barrier function is maintained by coordination of cell proliferation and cell loss, whereas barrier dysfunction can lead to disease and organismal death. JNK signalling is a conserved stress signalling pathway activated by bacterial infection and tissue damage, often leading to apoptotic cell death and compensatory cell proliferation. Here we show that the stress inducible transcription factor ATF3 restricts JNK activity in the Drosophila midgut. ATF3 regulates JNK-dependent apoptosis and regeneration through the transcriptional regulation of the JNK antagonist, Raw. Enterocyte-specific ATF3 inactivation increases JNK activity and sensitivity to infection, a phenotype that can be rescued by Raw overexpression or JNK suppression. ATF3 depletion enhances intestinal regeneration triggered by infection, but does not compensate for the loss of enterocytes and ATF3-depleted flies succumb to infection due to intestinal barrier dysfunction. In sum, we provide a mechanism to explain how an ATF3-Raw module controls JNK signalling to maintain normal intestinal barrier function during acute infection.
authors.affiliation: German Cancer Research Center (DKFZ), Division Signaling and Functional Genomics and Heidelberg University, Department for Cell and Molecular Biology, Medical Faculty Mannheim, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
authors.forename: Jun
authors.identifier: 0000-0002-2101-9304
authors.initials: J
authors.lastname: Zhou
authors.affiliation: German Cancer Research Center (DKFZ)-Center for Molecular Biology Heidelberg (ZMBH) Alliance, 69120 Heidelberg, Germany.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Edgar
authors.affiliation: German Cancer Research Center (DKFZ), Division Signaling and Functional Genomics and Heidelberg University, Department for Cell and Molecular Biology, Medical Faculty Mannheim, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
authors.forename: Michael
authors.identifier: 0000-0002-9458-817X
authors.initials: M
authors.lastname: Boutros
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D049109:Cell Proliferation; D002470:Cell Survival; D003598:Cytoskeletal Proteins / Q000235:genetics; D004198:Disease Susceptibility; D029721:Drosophila Proteins / Q000235:genetics; D004331:Drosophila melanogaster / Q000235:genetics; D020895:Enterocytes / Q000166:cytology; D005260:Female; D006706:Homeostasis; D007422:Intestines / Q000166:cytology / Q000502:physiology* / Q000503:physiopathology; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008938:Mitosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012038:Regeneration; D015398:Signal Transduction; D013312:Stress, Physiological; D014158:Transcription, Genetic
chemical_list: D051700:Activating Transcription Factor 3; D003598:Cytoskeletal Proteins; D029721:Drosophila Proteins; D047428:Protein Kinase Inhibitors; C115863:raw protein, Drosophila; D048670:MAP Kinase Kinase 4