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.

Adam J. Shaywitz,1,2 Kevin D. Courtney,1,3 Akash Patnaik,1,4 and Lewis C. Cantley1,5,* 1Division of Signal Transduction 2Division of Endocrinology Beth Israel Deaconess Medical Center, Boston, MA 02215, USA 3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA 4Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA 5Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA *Correspondence: lewis_cantley@hms.harvard.edu DOI 10.1016/j.cmet.2008.08.011