Without AHSP, globin inclusion bodies (purple) form.


In the absence of a binding partner, such as when β-globin is mutated in β-thalassemia, the unstable α-globin protein tends to form toxic inclusion bodies. Molecular chaperones that stabilize hemoglobin have been proposed to exist, but have not been found, until now. Anthony Kihm, Mitchell Weiss, and colleagues (University of Pennsylvania, Philadelphia, PA) have now identified a protein that protects α-globin until it can find β-globin and form hemoglobin A (HbA).

This chaperone-like protein, AHSP, was identified in a screen for genes induced by the transcription factor GATA-1, which promotes erythrocyte differentiation. Many genes were induced by GATA-1, but Weiss found AHSP particularly interesting because it was strongly and specifically expressed in RBCs and had no known function. Screens for protein–protein interactions revealed that AHSP bound to α-globin, but not to β-globin or HbA.

AHSP prevented α-globin precipitation in cells and in vitro. In mice lacking AHSP, erythrocytes contained inclusion bodies and turned over more rapidly than in wild-type mice. “The phenotype of the knock-out mice was relatively mild, probably because red cells do a good job of balancing the amount of α- and β-globin they produce,” says Weiss. “So, AHSP is not absolutely essential when things are good, but may become more important when things aren't going so well.”

Thus, AHSP could be a genetic modifier of β-thalassemia. Patients with this disease suffer twofold from a lack of β-globin—they are unable to make enough HbA for good respiratory capacity, and they have an excess of toxic, free α-globin. If a drug could be made to mimic AHSP, it might help offset free α-globin toxicity. This could decrease transfusion requirements in some patients. ▪


Kihm, A.J., et al.