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Hexokinase-II positively regulates glucose starvation-induced autophagy through TORC1 inhibition

David J Roberts1, Valerie P Tan-Sah1, Eric Y Ding1

  • 1Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA.

Molecular Cell
|January 28, 2014
PubMed

Insights

Hexokinase-II (HK-II) regulates protective autophagy by inhibiting mTORC1, a key suppressor. This mechanism switches cells from energy production to conservation during starvation.

Area of Science:

  • Cellular metabolism
  • Autophagy regulation
  • Molecular signaling

Background:

  • Hexokinase-II (HK-II) is crucial for glycolysis and cellular protection.
  • The role of HK-II in autophagy, a cellular self-degradation process, remains unclear.

Purpose of the Study:

  • To investigate the function of Hexokinase-II (HK-II) in regulating protective autophagy.
  • To elucidate the molecular mechanism by which HK-II influences autophagy.

Main Methods:

  • Utilized glucose deprivation to induce autophagy in cell models.
  • Employed immunoprecipitation to study protein interactions.
  • Introduced mutations in HK-II to assess functional impact.

Main Results:

  • HK-II inhibition reduced autophagy, while overexpression enhanced it.
  • HK-II directly binds to and inhibits mTOR complex 1 (TORC1), a known autophagy suppressor.
  • This interaction is strengthened by glucose deprivation and mediated by the TOS motif in HK-II.

Conclusions:

  • HK-II acts as a protective molecule by inhibiting TORC1, thereby promoting autophagy.
  • A novel mechanism is identified where HK-II functions as a decoy substrate for TORC1.
  • This pathway facilitates the metabolic switch from glycolysis to autophagy under nutrient-scarce conditions.

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