Erythrocyte precursors produce abundant alpha- and
beta-globin proteins, which assemble with each other to form
hemoglobin A (HbA), the major blood
oxygen carrier. alphaHb-stabilizing
protein (AHSP) binds free alpha subunits reversibly to maintain their structure and limit their ability to generate
reactive oxygen species. Accordingly, loss of AHSP aggravates the toxicity of excessive free
alpha-globin caused by
beta-globin gene disruption in mice. Surprisingly, we found that AHSP also has important functions when free
alpha-globin is limited. Thus, compound mutants lacking both Ahsp and 1 of 4
alpha-globin genes (genotype Ahsp(-/-)
alpha-globin*(alpha/alphaalpha)) exhibited more severe
anemia and Hb instability than mice with either mutation alone. In vitro, recombinant AHSP promoted folding of newly translated
alpha-globin, enhanced its refolding after denaturation, and facilitated its incorporation into HbA. Moreover, in erythroid precursors, newly formed free
alpha-globin was destabilized by loss of AHSP. Therefore, in addition to its previously defined role in detoxification of excess
alpha-globin, AHSP also acts as a
molecular chaperone to stabilize nascent
alpha-globin for HbA assembly. Our findings illustrate what we believe to be a novel adaptive mechanism by which a specialized cell coordinates high-level production of a multisubunit
protein and protects against various synthetic imbalances.