title: Molecular basis of insulin-responsive GLUT4 trafficking systems revealed by single molecule imaging.
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.
authors.affiliation: Graduate School of Biomedical Engineering, Tohoku University, Sendai, Miyagi 980-8575, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Hatakeyama
authors.forename: Makoto
authors.initials: M
authors.lastname: Kanzaki
mesh_terms: D041721:3T3-L1 Cells; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D050156:Adipogenesis / Q000502:physiology; D000818:Animals; D001324:Autoantigens / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D011992:Endosomes / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D000077614:Golgi Matrix Proteins; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D051379:Mice; D021381:Protein Transport / Q000502:physiology*; D050765:Qa-SNARE Proteins / Q000378:metabolism; D022161:Transport Vesicles / Q000378:metabolism; D021601:trans-Golgi Network / Q000378:metabolism; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D001324:Autoantigens; D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D000077614:Golgi Matrix Proteins; D007328:Insulin; D050765:Qa-SNARE Proteins; D000099183:Sortilin; C450721:Golgi complex autoantigen, 97-kDa; C495693:Slc2a4 protein, mouse; C505647:Tbc1d4 protein, mouse