A Phosphoinositide Interacting Protein Coordinates Stress Precursor Activities

Samd14 coordinates stem cell factor/Kit receptor signaling and is crucial for the survivalof red blood cel precursors within anemia contexts. Here we present new findings that Samd14 expression is needed to maintain balanced autophagy in red blood cell precursors following acute anemia. Autophagy gene signatures and protein levels are markedly altered withinthe context of acute anemia when red blood cell precursors accelerate the process of erythropoiesis. Samd14 interacted via its SAM domain with phosphatidylinositol 3-phosphate (PI3P) which is an integral component of endosomal and autophagic membranes. We tested PI3Ps role in red blood cell differentiation using a small molecule inhibitor of the Class III PI 3-kinase VPS34, which is the sole kinase responsible for PI3P genesis. SAR405 treatment blocked red blood cell formation. In the absence of Samd14, higher doses of VPS34 inhibition were required to block erythroid 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.