Hexokinase-II inhibits TORC1 to induce protective autophagy in response to glucose deprivation.
Major finding: Hexokinase-II inhibits TORC1 to induce protective autophagy in response to glucose deprivation.
Mechanism: Hexokinase-II directly binds to and inhibits the activity of TORC1 via its TOS motif.
Impact: Hexokinase-II regulates the switch from glycolysis to autophagy during nutrient starvation.
Hexokinases (HK) play a key role in energy metabolism by catalyzing the first step in glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G-6P). HK-II, which is upregulated in most tumors, is the predominant isoform expressed in the heart, where it has been implicated in cardiomyocyte cell survival. In the heart, glucose deprivation activates autophagy to confer cardioprotection, but the mechanism of signal integration between glycolysis and autophagy is not well understood. Roberts and colleagues found that inhibition of HK-II activity blocked glucose starvation-induced autophagy in rat cardiomyocytes as well as in other cell types. Modulation of HK-II, but not HK-I, levels by knockdown or overexpression, respectively, inhibited or potentiated glucose starvation-induced autophagy, indicating that regulation of glucose starvation-induced autophagy is an HK-II–specific function. HK-II inhibition by knockdown or treatment with the glucose analogue 2-deoxy-D-glucose also caused an increase in apoptosis induced by glucose deprivation, suggesting that HK-II–mediated autophagy confers protection from glucose starvation. Interestingly, glucose deprivation induced a HK-II–dependent decrease in phosphorylation of substrates of the mTOR complex 1 (TORC1), a known suppressor of autophagy. In response to glucose deprivation, HK-II bound to TORC1 via a conserved mTOR signaling (TOS) motif, and mutation of this motif abolished HK-II–mediated induction of autophagy. The catalytic activity of HK-II was not necessary for TORC1 inhibition, implying that HK-II negatively regulates TORC1 by acting as a binding protein. Instead, the glycolytic activity of HK-II inhibited its autophagic function, as production of G-6P inhibited glucose deprivation-induced autophagy. Although further characterization of the mechanism by which HK-II inhibits TORC1 is warranted, these findings identify HK-II as a critical sensor of glucose depletion that regulates the switch from glycolysis to protective autophagy during nutrient starvation.
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