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Letters to Nature

Nature 425, 727-733 (16 October 2003) | doi:10.1038/nature01989; Received 17 June 2003; Accepted 4 August 2003

Functional cloning of TUG as a regulator of GLUT4 glucose transporter trafficking

Jonathan S. Bogan1,2,3,5, Natalie Hendon1,2, Adrienne E. McKee1,5, Tsu-Shuen Tsao1 & Harvey F. Lodish1,4

  1. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA
  2. Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02129, USA
  3. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA
  4. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA
  5. Present addresses: Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, Box 208020, New Haven, Connecticut 06520-8020, USA (J.S.B.); Program in Biological and Biomedical Sciences, Harvard Medical School, 220 Longwood Ave, Boston, Massachusetts 02115, USA (A.E.M.)

Correspondence to: Jonathan S. Bogan1,2,3,5 Email: jonathan.bogan@yale.edu
The cDNA sequences of the short and long TUG forms have been deposited in GenBank under accession numbers AY349132 and AY349133, respectfully.

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Insulin stimulates glucose uptake in fat and muscle by mobilizing the GLUT4 glucose transporter. GLUT4 is sequestered intracellularly in the absence of insulin, and is redistributed to the plasma membrane within minutes of insulin stimulation1, 2. But the trafficking mechanisms that control GLUT4 sequestration have remained elusive. Here we describe a functional screen to identify proteins that modulate GLUT4 distribution, and identify TUG as a putative tether, containing a UBX domain, for GLUT4. In truncated form, TUG acts in a dominant-negative manner to inhibit insulin-stimulated GLUT4 redistribution in Chinese hamster ovary cells and 3T3-L1 adipocytes. Full-length TUG forms a complex specifically with GLUT4; in 3T3-L1 adipocytes, this complex is present in unstimulated cells and is largely disassembled by insulin. Endogenous TUG is localized with the insulin-mobilizable pool of GLUT4 in unstimulated 3T3-L1 adipocytes, and is not mobilized to the plasma membrane by insulin. Distinct regions of TUG are required to bind GLUT4 and to retain GLUT4 intracellularly in transfected, non-adipose cells. Our data suggest that TUG traps endocytosed GLUT4 and tethers it intracellularly, and that insulin mobilizes this pool of retained GLUT4 by releasing this tether.