Autophagy inhibition in intestinal stem cells favors enteroendocrine cell differentiation through Stat92E activity

Abstract

ABSTRACTBecause the intestinal epithelium faces many stresses, dysregulation of essential mechanisms governing gut homeostasis, such as autophagy, has been associated with inflammatory bowel pathologies. InDrosophila melanogaster, the inhibition of autophagy, specifically in adult intestinal stem cells (ISCs), affects their number differently through aging. Appropriate intestinal renewal requires a balance between ISC proliferation and differentiation. Herein, we show that in adult ISCs, the loss of core autophagy genes and regulators of autophagosome-lysosome fusion increased the enteroendocrine cell population and transcriptional activity of Stat92E. Functional experiments with cell fate regulators involved in enteroendocrine or enterocyte differentiation or proliferation suggested that dysfunctional autophagy in adult ISCs enhanced Stat92E activity downstream of Hop/JAK kinase. Finally, lineage-tracing analyses confirmed that autophagy inhibition autonomously promotes enteroendocrine cell differentiation without affecting enterocyte differentiation. Thus, our data demonstrates that, under homeostatic conditions, basal autophagy limits enteroendocrine cell differentiation by controlling Stat92E activity.