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SLC2A8 (GLUT8) is a mammalian trehalose transporter required for trehalose-induced autophagy.

Identifieur interne : 000A19 ( Main/Exploration ); précédent : 000A18; suivant : 000A20

SLC2A8 (GLUT8) is a mammalian trehalose transporter required for trehalose-induced autophagy.

Auteurs : Allyson L. Mayer [États-Unis] ; Cassandra B. Higgins [États-Unis] ; Monique R. Heitmeier [États-Unis] ; Thomas E. Kraft [États-Unis] ; Xia Qian [États-Unis] ; Jan R. Crowley [États-Unis] ; Krzysztof L. Hyrc [États-Unis] ; Wandy L. Beatty [États-Unis] ; Kevin E. Yarasheski [États-Unis] ; Paul W. Hruz [États-Unis] ; Brian J. Debosch [États-Unis]

Source :

RBID : pubmed:27922102

Descripteurs français

English descriptors

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.

DOI: 10.1038/srep38586
PubMed: 27922102
PubMed Central: PMC5138640


Affiliations:


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<series>
<title level="j">Scientific reports</title>
<idno type="eISSN">2045-2322</idno>
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<keywords scheme="KwdEn" xml:lang="en">
<term>AMP-Activated Protein Kinases (metabolism)</term>
<term>Amino Acid Sequence (MeSH)</term>
<term>Animals (MeSH)</term>
<term>Autophagy (drug effects)</term>
<term>Biological Transport (MeSH)</term>
<term>Cell Line (MeSH)</term>
<term>Fatty Acids (metabolism)</term>
<term>Glucose (metabolism)</term>
<term>Glucose Transport Proteins, Facilitative (chemistry)</term>
<term>Glucose Transport Proteins, Facilitative (genetics)</term>
<term>Glucose Transport Proteins, Facilitative (metabolism)</term>
<term>Hepatocytes (metabolism)</term>
<term>Humans (MeSH)</term>
<term>Mechanistic Target of Rapamycin Complex 1 (metabolism)</term>
<term>Mice (MeSH)</term>
<term>Mice, Knockout (MeSH)</term>
<term>Models, Biological (MeSH)</term>
<term>Models, Molecular (MeSH)</term>
<term>Molecular Conformation (MeSH)</term>
<term>Phosphorylation (MeSH)</term>
<term>Protein Binding (MeSH)</term>
<term>Signal Transduction (MeSH)</term>
<term>Trehalose (chemistry)</term>
<term>Trehalose (metabolism)</term>
<term>Trehalose (pharmacology)</term>
<term>Triglycerides (metabolism)</term>
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<term>AMP-Activated Protein Kinases (métabolisme)</term>
<term>Acides gras (métabolisme)</term>
<term>Animaux (MeSH)</term>
<term>Autophagie (effets des médicaments et des substances chimiques)</term>
<term>Complexe-1 cible mécanistique de la rapamycine (métabolisme)</term>
<term>Conformation moléculaire (MeSH)</term>
<term>Glucose (métabolisme)</term>
<term>Humains (MeSH)</term>
<term>Hépatocytes (métabolisme)</term>
<term>Liaison aux protéines (MeSH)</term>
<term>Lignée cellulaire (MeSH)</term>
<term>Modèles biologiques (MeSH)</term>
<term>Modèles moléculaires (MeSH)</term>
<term>Phosphorylation (MeSH)</term>
<term>Souris (MeSH)</term>
<term>Souris knockout (MeSH)</term>
<term>Séquence d'acides aminés (MeSH)</term>
<term>Transduction du signal (MeSH)</term>
<term>Transport biologique (MeSH)</term>
<term>Transporteurs de glucose par diffusion facilitée (composition chimique)</term>
<term>Transporteurs de glucose par diffusion facilitée (génétique)</term>
<term>Transporteurs de glucose par diffusion facilitée (métabolisme)</term>
<term>Triglycéride (métabolisme)</term>
<term>Tréhalose (composition chimique)</term>
<term>Tréhalose (métabolisme)</term>
<term>Tréhalose (pharmacologie)</term>
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<term>Trehalose</term>
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<term>Glucose Transport Proteins, Facilitative</term>
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<term>Fatty Acids</term>
<term>Glucose</term>
<term>Glucose Transport Proteins, Facilitative</term>
<term>Mechanistic Target of Rapamycin Complex 1</term>
<term>Trehalose</term>
<term>Triglycerides</term>
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<term>Transporteurs de glucose par diffusion facilitée</term>
<term>Tréhalose</term>
</keywords>
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<term>Autophagy</term>
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<term>Autophagie</term>
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<term>Transporteurs de glucose par diffusion facilitée</term>
</keywords>
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<term>Hepatocytes</term>
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<term>AMP-Activated Protein Kinases</term>
<term>Acides gras</term>
<term>Complexe-1 cible mécanistique de la rapamycine</term>
<term>Glucose</term>
<term>Hépatocytes</term>
<term>Transporteurs de glucose par diffusion facilitée</term>
<term>Triglycéride</term>
<term>Tréhalose</term>
</keywords>
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<term>Tréhalose</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en">
<term>Trehalose</term>
</keywords>
<keywords scheme="MESH" xml:lang="en">
<term>Amino Acid Sequence</term>
<term>Animals</term>
<term>Biological Transport</term>
<term>Cell Line</term>
<term>Humans</term>
<term>Mice</term>
<term>Mice, Knockout</term>
<term>Models, Biological</term>
<term>Models, Molecular</term>
<term>Molecular Conformation</term>
<term>Phosphorylation</term>
<term>Protein Binding</term>
<term>Signal Transduction</term>
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<keywords scheme="MESH" xml:lang="fr">
<term>Animaux</term>
<term>Conformation moléculaire</term>
<term>Humains</term>
<term>Liaison aux protéines</term>
<term>Lignée cellulaire</term>
<term>Modèles biologiques</term>
<term>Modèles moléculaires</term>
<term>Phosphorylation</term>
<term>Souris</term>
<term>Souris knockout</term>
<term>Séquence d'acides aminés</term>
<term>Transduction du signal</term>
<term>Transport biologique</term>
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<div type="abstract" xml:lang="en">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.</div>
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<AbstractText>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.</AbstractText>
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