Proposed roles of HRI signaling pathway in stress erythropoiesis. Upon stress in erythroid cells, HRI is activated first to inhibit protein synthesis in order to reduce toxic globin precipitates. We propose that HRI also participates in the second arm of defense by increasing expression of specific genes such as Chop and GADD34, necessary for the adaptation to stress conditions. However, when the stress is insurmountable, this signaling pathway can also lead to apoptosis. In the absence of HRI, excess globins form inclusions and lead to hemolysis as well as apoptosis of erythroid precursors. Consequently, ineffective erythropoiesis occurs.