Protein quality control during erythropoiesis and hemoglobin synthesis.

Erythrocytes must regulate hemoglobin synthesis to limit the toxicities of unstable free globin chain subunits. This regulation is particularly relevant in β-thalassemia, in which β-globin deficiency causes accumulation of free α-globin, which forms intracellular precipitates that destroy erythroid precursors. Experimental evidence accumulated over more than 40 years indicates that erythroid cells can neutralize moderate amounts of free α-globin through generalized protein quality control mechanisms, including molecular chaperones, the ubiquitin-proteasome system, and autophagy. In many ways, β-thalassemia resembles protein aggregation disorders of the nervous system, liver, and other tissues, which occur when levels of unstable proteins overwhelm cellular compensatory mechanisms. Information gained from studies of nonerythroid protein aggregation disorders may be exploited to further understand and perhaps treat β-thalassemia.