Homeostatic Regulation of ROS-Triggered Hippo-Yki Pathway via Autophagic Clearance of Ref(2)P/p62 in the Drosophila Intestine

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. [Display omitted] •Commensals trigger chronic regenerative responses in autophagy-deficient enterocytes•Luminal ROS induce inactivation of Hippo signaling via Ref(2)P oligomerization•Ref(2)P-Dachs punctate structure accumulates in autophagy-defective enterocytes•Ref(2)P-mediated regenerative signaling accelerates age-related intestinal disorders Autophagy is essential for maintaining homeostasis in the Drosophila intestine. Nagai et al. show that ROS secreted from epithelial cells in response to commensal bacteria continuously stimulate regeneration, which is suppressed by host autophagy. Autophagy defect causes Ref(2)P/p62-mediated Hippo pathway inactivation in enterocytes, resulting in accelerated age-related intestinal disorders.