A stress-induced PI3P complex controls autophagy in erythroid precursors.

Samd14 coordinates stem cell factor/Kit receptor signaling and is crucial for the survival of erythroid precursors in anemia contexts. Here, we show that Samd14 is needed to maintain balanced autophagy in erythroid precursors following acute anemia. Autophagy-associated gene signatures and protein levels are deregulated when erythropoiesis accelerates in acute anemia. Mechanistically, Samd14 interacts via its SAM domain with phosphatidylinositol 3-phosphate (PI3P), an integral component of endosomal and autophagic membranes. Pharmacologic inhibition of VPS34, the class III PI 3-kinase that generates PI3P, impaired erythroid differentiation specifically in stress contexts. Loss of Samd14 shifted the sensitivity of erythroid precursors to VPS34 inhibition, where higher doses were required to block differentiation. Given the critical roles of autophagy in normal differentiation, Samd14's stress-dependent activation and roles in autophagy suggest that this mechanism is needed to maintain progenitor levels and balance the production of healthy, mature red blood cells in anemia.