Molecular Basis of Insulin-Responsive GLUT4 Trafficking Systems Revealed by Single Molecule Imaging

Hiroyasu Hatakeyama, Makoto Kanzaki

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1805-1820
Number of pages16
JournalTraffic
Volume12
Issue number12
DOIs
Publication statusPublished - 2011 Dec

Keywords

  • AS160/Tbc1d4
  • Insulin resistance
  • Quantum dot
  • Retromer
  • Sortilin
  • Sorting disorder
  • TGN-golgin
  • Trans-Golgi network

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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