title: AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1.
abstract: Thioredoxin-interacting protein (TXNIP) is an α-arrestin family protein that is induced in response to glucose elevation. It has been shown to provide a negative feedback loop to regulate glucose uptake into cells, though the biochemical mechanism of action has been obscure. Here, we report that TXNIP suppresses glucose uptake directly, by binding to the glucose transporter GLUT1 and inducing GLUT1 internalization through clathrin-coated pits, as well as indirectly, by reducing the level of GLUT1 messenger RNA (mRNA). In addition, we show that energy stress results in the phosphorylation of TXNIP by AMP-dependent protein kinase (AMPK), leading to its rapid degradation. This suppression of TXNIP results in an acute increase in GLUT1 function and an increase in GLUT1 mRNA (hence the total protein levels) for long-term adaptation. The glucose influx through GLUT1 restores ATP-to-ADP ratios in the short run and ultimately induces TXNIP protein production to suppress glucose uptake once energy homeostasis is reestablished.
authors: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
authors: Ning
authors: N
authors: Wu
authors: Bin
authors: B
authors: Zheng
authors: Adam
authors: A
authors: Shaywitz
authors: Yossi
authors: Y
authors: Dagon
authors: Christine
authors: C
authors: Tower
authors: Gary
authors: G
authors: Bellinger
authors: Che-Hung
authors: CH
authors: Shen
authors: Jennifer
authors: J
authors: Wen
authors: John
authors: J
authors: Asara
authors: Timothy E
authors: TE
authors: McGraw
authors: Barbara B
authors: BB
authors: Kahn
authors: Lewis C
authors: LC
authors: Cantley
mesh_terms: D000263:Adenylate Kinase / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D022163:Clathrin-Coated Vesicles / Q000378:metabolism; D017124:Conserved Sequence; D004705:Endocytosis; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D021381:Protein Transport; D059748:Proteolysis; D059008:Time-Lapse Imaging
chemical_list: D002352:Carrier Proteins; D051272:Glucose Transporter Type 1; C495677:SLC2A1 protein, human; C486715:TXNIP protein, human; D000263:Adenylate Kinase; D005947:Glucose