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.
Highlights
Epithelial barrier function is maintained by coordination of cell proliferation and cell loss, whereas barrier dysfunction can lead to disease and organismal death
Previous studies in the Drosophila midgut showed that intestinal stem cells (ISC) proliferate rapidly to produce new entoerocytes for epithelial renewal, and that homeostasis is maintained by activating JNK, EGFR, JAK/STAT and BMP signalling pathways, which are activated in response to oxidative stress, bacterial infection and ingestion of toxins such as dextran sodium sulfate or bleomycin[9,19,20,21,22,23,24,25,26,27,28,29]
We found that enterocytes with large-nuclei showed a strong GFP-signal, while Delta-positive stem cells (ISCs) were only weakly GFP-positive
Summary
Epithelial barrier function is maintained by coordination of cell proliferation and cell loss, whereas barrier dysfunction can lead to disease and organismal death. Dysregulation of stress, immune and inflammatory signalling, and stem cell proliferation result in impaired epithelial renewal and subsequent barrier dysfunction, which increases animal mortality. It is mostly unknown how apoptotic signalling and stem cell activity (for example, after infection with pathogens) is buffered to prevent barrier dysfunction of the epithelium. JNK influences Drosophila gut regeneration by promoting stem cell proliferation[25,30], and activated JNK can cause apoptosis of enterocytes[11], indicating that JNK signalling has a complex function in tissue homeostasis. Our study uncovers an essential autonomous role of ATF3Raw-JNK signalling in controlling cell survival and stress responses in intestinal enterocytes
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