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Mol Cell. 2014 Feb 20;53(4):521-33. doi: 10.1016/j.molcel.2013.12.019. Epub 2014 Jan 23.

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

Author information

1
Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA.
2
Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA. Electronic address: smiyamoto@ucsd.edu.

Abstract

Hexokinase-II (HK-II) catalyzes the first step of glycolysis and also functions as a protective molecule; however, its role in protective autophagy has not been determined. Results showed that inhibition of HK-II diminished, while overexpression of HK-II potentiated, autophagy induced by glucose deprivation in cardiomyocyte and noncardiomyocyte cells. Immunoprecipitation studies revealed that HK-II binds to and inhibits the autophagy suppressor, mTOR complex 1 (TORC1), and that this binding was increased by glucose deprivation. The TOS motif, a scaffold sequence responsible for binding TORC1 substrates, is present in HK-II, and mutating it blocked its ability to bind to TORC1 and regulate protective autophagy. The transition from glycolysis to autophagy appears to be regulated by a decrease in glucose-6 phosphate. We suggest that HK-II binds TORC1 as a decoy substrate and provides a previously unrecognized mechanism for switching cells from a metabolic economy, based on plentiful energy, to one of conservation, under starvation.

PMID:
24462113
PMCID:
PMC3943874
DOI:
10.1016/j.molcel.2013.12.019
[Indexed for MEDLINE]
Free PMC Article

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