1. Homeostatic Regulation of ROS-Triggered Hippo-Yki Pathway via Autophagic Clearance of Ref(2)P/p62 in the Drosophila Intestine.
- Author
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Nagai H, Tatara H, Tanaka-Furuhashi K, Kurata S, and Yano T
- Subjects
- Aging metabolism, Animals, Animals, Genetically Modified, Autophagy drug effects, Autophagy genetics, Cell Proliferation genetics, DNA-Binding Proteins genetics, Dextran Sulfate toxicity, Drosophila genetics, Drosophila immunology, Drosophila physiology, Drosophila Proteins genetics, Enterocytes metabolism, Gene Knockdown Techniques, Genome-Wide Association Study, Homeostasis, Immunohistochemistry, Inhibitor of Apoptosis Proteins genetics, Inhibitor of Apoptosis Proteins metabolism, Intestinal Mucosa cytology, Intestinal Mucosa drug effects, Intestines cytology, Intestines drug effects, Intracellular Signaling Peptides and Proteins genetics, Muscle Proteins, Myosins genetics, Myosins metabolism, Nuclear Proteins genetics, Protein Serine-Threonine Kinases genetics, Reactive Oxygen Species metabolism, Signal Transduction drug effects, Signal Transduction genetics, Trans-Activators genetics, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, YAP-Signaling Proteins, DNA-Binding Proteins metabolism, Drosophila metabolism, Drosophila Proteins metabolism, Intestinal Mucosa metabolism, Intracellular Signaling Peptides and Proteins metabolism, Nuclear Proteins metabolism, Protein Serine-Threonine Kinases metabolism, Stem Cells metabolism, Trans-Activators metabolism
- Abstract
Homeostasis of intestinal epithelia is maintained by coordination of the proper rate of regeneration by stem cell division with the rate of cell loss. Regeneration of host epithelia is normally quiescent upon colonization of commensal bacteria; however, the epithelia often develop dysplasia in a context-dependent manner, the cause and underlying mechanism of which remain unclear. Here, we show that in Drosophila intestine, autophagy lowers the sensitivity of differentiated enterocytes to reactive oxygen species (ROS) that are produced in response to commensal bacteria. We find that autophagy deficiency provokes ROS-dependent excessive regeneration and subsequent epithelial dysplasia and barrier dysfunction. Mechanistically, autophagic substrate Ref(2)P/p62, which co-localizes and physically interacts with Dachs, a Hippo signaling regulator, accumulates upon autophagy deficiency and thus inactivates Hippo signaling, resulting in stem cell over-proliferation non-cell autonomously. Our findings uncover a mechanism whereby suppression of undesirable regeneration by autophagy maintains long-term homeostasis of intestinal epithelia., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2021
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