Gcn5 – mTORC1 – TFEB signalling axis mediated control of autophagy regulates Drosophila blood cell homeostasis

Abstract

Blood progenitors are regulated by a variety of signals from their environment. In the Drosophila lymph gland (LG), the Posterior Signalling Center (PSC) acts as a stem cell niche striking a balance between progenitors and differentiated blood cells. While the response of blood progenitors to extrinsic signals is well characterized, their ability to respond to cell intrinsic cues is unexplored. Autophagy is one such intrinsic cellular process that maintains cellular homeostasis by removing unnecessary or dysfunctional cell components through autophagic degradation and recycling. Here, we show that autophagy plays a critical role in regulating blood cell homeostasis in the lymph gland. General control non-derepressible 5 (Gcn5), a histone acetyltransferase is expressed in all the cellular subsets of the LG and modulation of Gcn5 levels in various cellular subsets of the LG perturbs LG homeostasis. Gcn5 through its known non-histone acetylation target, TFEB controls autophagic flux thereby regulating hematopoiesis. Additionally, we demonstrate that modulation of mTORC1 activity can perturb hematopoiesis. We show that Gcn5 acts as a nutrient sensor and mTORC1 activity regulates Gcn5. mTORC1 over-rides the effect exerted by Gcn5 in regulating LG hematopoiesis. Together, our findings indicate that Gcn5 – mTORC1 – TFEB signaling axis mediated control of autophagy is required for maintaining blood cell homeostasis in Drosophila .