Model of α-globin detoxification pathways in β-thalassemia. Excess free α-globin is unstable and cytotoxic to RBC precursors and mature RBCs. Unstable α-globin is polyubiquitinated and degraded via the proteasome. If ubiquitin-proteasome activity is insufficient, α-globin forms relatively insoluble aggregates that serve as a substrate for macroautophagy. Chaperones may be involved in refolding α-globin or in targeting excess α-globin for degradation. Molecular cross-talk exists between these pathways; for example, inhibition of proteasome activity results in the accumulation of unfolded proteins, activation of stress pathways, and consequent induction of autophagy and heat-shock/molecular chaperone responses.