The incredible ULK improves β-thalassemia

In this issue of Blood, Keith and colleagues show the miR-144/451 locus is a genetic modifier of beta-thalassemia by regulating removal of free alpha-globin via the autophagy kinase ULK1 (Unc-51-like autophagy-activating kinase 1).1 miR-144/451 is the highest expressed miR locus in terminal erythroid differentiation, and its disruption in a beta-thalassemia mouse model releases inhibition of the Cab39/Strad/LKB1 complex. Increased expression of Cab39/ Strad/LKB1 activates adenosine monophosphate-activated protein kinase (AMPK), sometimes referred to as the "cellular fuel gauge." Increased AMPK signaling reduces mammalian target of rapamycin complex 1 (mTORC1)mediated repression of ULK1 and directly activates ULK1 to give it super strength to degrade free alpha-globin, which, if it accumulates, is so toxic that it triggers apoptosis (see figure). The role of AMPK in this pathway suggests existing drugs that increase AMPK activity2 could be repurposed as part of a beta-thalassemia combination therapy.