RRC ID 64381
Author Nagai H, Tatara H, Tanaka-Furuhashi K, Kurata S, Yano T.
Title Homeostatic Regulation of ROS-Triggered Hippo-Yki Pathway via Autophagic Clearance of Ref(2)P/p62 in the Drosophila Intestine.
Journal Dev Cell
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.
Volume 56(1)
Pages 81-94.e10
Published 2021-1-11
DOI 10.1016/j.devcel.2020.12.007
PII S1534-5807(20)30982-5
PMID 33400912
MeSH Aging / metabolism Animals Animals, Genetically Modified Autophagy / drug effects Autophagy / genetics Cell Proliferation / genetics DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism* Dextran Sulfate / toxicity Drosophila / genetics Drosophila / immunology Drosophila / metabolism* Drosophila / physiology Drosophila Proteins / genetics Drosophila Proteins / metabolism* 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 Intestinal Mucosa / metabolism* Intestines / cytology Intestines / drug effects Intracellular Signaling Peptides and Proteins / genetics Intracellular Signaling Peptides and Proteins / metabolism* Muscle Proteins Myosins / genetics Myosins / metabolism Nuclear Proteins / genetics Nuclear Proteins / metabolism* Protein-Serine-Threonine Kinases / genetics Protein-Serine-Threonine Kinases / metabolism* Reactive Oxygen Species / metabolism Signal Transduction / drug effects Signal Transduction / genetics Stem Cells / metabolism* Trans-Activators / genetics Trans-Activators / metabolism* Tumor Suppressor Proteins / genetics Tumor Suppressor Proteins / metabolism
IF 10.092
Resource
Drosophila DGRC#112001 DGRC#109126