Hexokinase-II positively regulates glucose starvation-induced autophagy through TORC1 inhibition.
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.
Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA.
David J
DJ
Roberts
Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA.
Valerie P
VP
Tan-Sah
Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA.
Eric Y
EY
Ding
Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA.
Jeffery M
JM
Smith
Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA. Electronic address: smiyamoto@ucsd.edu.
Shigeki
S
Miyamoto
D020816:Amino Acid Motifs; D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D005508:Food Deprivation; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000378:metabolism*; D019298:Glucose-6-Phosphate / Q000378:metabolism; D006593:Hexokinase / Q000378:metabolism*; D047468:Immunoprecipitation; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D009154:Mutation; D032383:Myocytes, Cardiac / Q000201:enzymology*; D018384:Oxidative Stress; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D019298:Glucose-6-Phosphate; D006593:Hexokinase; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D005947:Glucose