title: SLC2A8 (GLUT8) is a mammalian trehalose transporter required for trehalose-induced autophagy.
abstract: Trehalose is a disaccharide demonstrated to mitigate disease burden in multiple murine neurodegenerative models. We recently revealed that trehalose rapidly induces hepatic autophagy and abrogates hepatic steatosis by inhibiting hexose transport via the SLC2A family of facilitative transporters. Prior studies, however, postulate that intracellular trehalose is sufficient to induce cellular autophagy. The objective of the current study was to identify the means by which trehalose accesses the hepatocyte cytoplasm, and define the distal signaling mechanisms by which trehalose induces autophagy. We provide gas chromatographic/mass spectrometric, fluorescence microscopic and radiolabeled uptake evidence that trehalose traverses the plasma membrane via SLC2A8 (GLUT8), a homolog of the trehalose transporter-1 (Tret1). Moreover, GLUT8-deficient hepatocytes and GLUT8-deficient mice exposed to trehalose resisted trehalose-induced AMP-activated protein kinase (AMPK) phosphorylation and autophagic induction in vitro and in vivo. Although trehalose profoundly attenuated mTORC1 signaling, trehalose-induced mTORC1 suppression was insufficient to activate autophagy in the absence of AMPK or GLUT8. Strikingly, transient, heterologous Tret1 overexpression reconstituted autophagic flux and AMPK signaling defects in GLUT8-deficient hepatocyte cultures. Together, these data suggest that cytoplasmic trehalose access is carrier-mediated, and that GLUT8 is a mammalian trehalose transporter required for hepatocyte trehalose-induced autophagy and signal transduction.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: Allyson L
authors.initials: AL
authors.lastname: Mayer
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: Cassandra B
authors.initials: CB
authors.lastname: Higgins
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: Monique R
authors.initials: MR
authors.lastname: Heitmeier
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Kraft
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Qian
authors.affiliation: Department of Medicine, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: Jan R
authors.initials: JR
authors.lastname: Crowley
authors.affiliation: Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.|The Hope Center for Neurological Disorders, Alafi Neuroimaging Laboratory, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: Krzysztof L
authors.initials: KL
authors.lastname: Hyrc
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: Wandy L
authors.initials: WL
authors.lastname: Beatty
authors.affiliation: Department of Medicine, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Yarasheski
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Hruz
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.|Department of Cell Biology &Physiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: DeBosch
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001692:Biological Transport; D002460:Cell Line; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051246:Glucose Transport Proteins, Facilitative / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D008958:Models, Molecular; D008968:Molecular Conformation; D010766:Phosphorylation; D011485:Protein Binding; D015398:Signal Transduction; D014199:Trehalose / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D051246:Glucose Transport Proteins, Facilitative; C405325:SLC2A8 protein, human; C498628:Slc2a8 protein, mouse; D014280:Triglycerides; D014199:Trehalose; D000076222:Mechanistic Target of Rapamycin Complex 1; D055372:AMP-Activated Protein Kinases; D005947:Glucose