Molecular basis of insulin-responsive GLUT4 trafficking systems revealed by single molecule imaging

Traffic. 2011 Dec;12(12):1805-20. doi: 10.1111/j.1600-0854.2011.01279.x. Epub 2011 Oct 9.

Abstract

Development of a 'static retention' property of GLUT4, the insulin-responsive glucose transporter, has emerged as being essential for achieving its maximal insulin-induced surface exposure. Herein, employing quantum-dot-based nanometrology of intracellular GLUT4 behavior, we reveal the molecular basis of its systematization endowed upon adipogenic differentiation of 3T3L1 cells. Specifically, (i) the endosomes-to-trans-Golgi network (TGN) retrieval system specialized for GLUT4 develops in response to sortilin expression, which requires an intricately balanced interplay among retromers, golgin-97 and syntaxin-6, the housekeeping vesicle trafficking machinery. (ii) The Golgin-97-localizing subdomain of the differentiated TGN apparently serves as an intermediate transit route by which GLUT4 can further proceed to the stationary GLUT4 storage compartment. (iii) AS160/Tbc1d4 then renders the 'static retention' property insulin responsive, i.e. insulin liberates GLUT4 from the static state only in the presence of functional AS160/Tbc1d4. (iv) Moreover, sortilin malfunction and the resulting GLUT4 sorting defects along with retarded TGN function might be etiologically related to insulin resistance. Together, these observations provide a conceptual framework for understanding maturation/retardation of the insulin-responsive GLUT4 trafficking system that relies on the specialized subdomain of differentiated TGN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism
  • Adipogenesis / physiology
  • Animals
  • Autoantigens / metabolism
  • Cell Differentiation / physiology
  • Endosomes / metabolism
  • GTPase-Activating Proteins / metabolism
  • Glucose Transporter Type 4 / metabolism*
  • Golgi Matrix Proteins
  • Humans
  • Insulin / metabolism*
  • Insulin Resistance / physiology
  • Mice
  • Protein Transport / physiology*
  • Qa-SNARE Proteins / metabolism
  • Transport Vesicles / metabolism
  • trans-Golgi Network / metabolism

Substances

  • Adaptor Proteins, Vesicular Transport
  • Autoantigens
  • GTPase-Activating Proteins
  • Glucose Transporter Type 4
  • Golgi Matrix Proteins
  • Golgi complex autoantigen, 97-kDa
  • Insulin
  • Qa-SNARE Proteins
  • Slc2a4 protein, mouse
  • Tbc1d4 protein, mouse
  • sortilin