The deubiquitinating enzyme USP25 binds tankyrase and regulates trafficking of the facilitative glucose transporter GLUT4 in adipocytes

TY - JOUR

T1 - The deubiquitinating enzyme USP25 binds tankyrase and regulates trafficking of the facilitative glucose transporter GLUT4 in adipocytes

AU - Sadler, Jessica B A

AU - Lamb, Christopher A

AU - Welburn, Cassie R

AU - Adamson, Iain S

AU - Kioumourtzoglou, Dimitrios

AU - Chi, Nai-Wen

AU - Gould, Gwyn W

AU - Bryant, Nia J

N1 - This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

PY - 2019/3/18

Y1 - 2019/3/18

N2 - Key to whole body glucose homeostasis is the ability of fat and muscle cells to sequester the facilitative glucose transporter GLUT4 in an intracellular compartment from where it can be mobilized in response to insulin. We have previously demonstrated that this process requires ubiquitination of GLUT4 while numerous other studies have identified several molecules that are also required, including the insulin-responsive aminopeptidase IRAP and its binding partner, the scaffolding protein tankyrase. In addition to binding IRAP, Tankyrase has also been shown to bind the deubiquinating enzyme USP25. Here we demonstrate that USP25 and Tankyrase interact, and colocalise with GLUT4 in insulin-sensitive cells. Furthermore depletion of USP25 from adipocytes reduces cellular levels of GLUT4 and concomitantly blunts the ability of insulin to stimulate glucose transport. Collectively, these data support our model that sorting of GLUT4 into its insulin-sensitive store involves a cycle of ubiquitination and subsequent deubiquitination.

AB - Key to whole body glucose homeostasis is the ability of fat and muscle cells to sequester the facilitative glucose transporter GLUT4 in an intracellular compartment from where it can be mobilized in response to insulin. We have previously demonstrated that this process requires ubiquitination of GLUT4 while numerous other studies have identified several molecules that are also required, including the insulin-responsive aminopeptidase IRAP and its binding partner, the scaffolding protein tankyrase. In addition to binding IRAP, Tankyrase has also been shown to bind the deubiquinating enzyme USP25. Here we demonstrate that USP25 and Tankyrase interact, and colocalise with GLUT4 in insulin-sensitive cells. Furthermore depletion of USP25 from adipocytes reduces cellular levels of GLUT4 and concomitantly blunts the ability of insulin to stimulate glucose transport. Collectively, these data support our model that sorting of GLUT4 into its insulin-sensitive store involves a cycle of ubiquitination and subsequent deubiquitination.

KW - 3T3-L1 Cells

KW - Adipocytes/cytology

KW - Animals

KW - Cell Membrane/metabolism

KW - Cystinyl Aminopeptidase/metabolism

KW - Gene Knockdown Techniques

KW - Glucose/metabolism

KW - Glucose Transporter Type 4/metabolism

KW - Insulin/metabolism

KW - Mice

KW - Tankyrases/metabolism

KW - Ubiquitin Thiolesterase/genetics

KW - Ubiquitination

U2 - 10.1038/s41598-019-40596-5

DO - 10.1038/s41598-019-40596-5

M3 - Article

C2 - 30886164

SN - 2045-2322

VL - 9

SP - 4710

JO - Scientific Reports

JF - Scientific Reports

IS - 1

ER -