title: PICK1 and ICA69 control insulin granule trafficking and their deficiencies lead to impaired glucose tolerance.
abstract: Diabetes is a metabolic disorder characterized by hyperglycemia. Insulin, which is secreted by pancreatic beta cells, is recognized as the critical regulator of blood glucose, but the molecular machinery responsible for insulin trafficking remains poorly defined. In particular, the roles of cytosolic factors that govern the formation and maturation of insulin granules are unclear. Here we report that PICK1 and ICA69, two cytosolic lipid-binding proteins, formed heteromeric BAR-domain complexes that associated with insulin granules at different stages of their maturation. PICK1-ICA69 heteromeric complexes associated with immature secretory granules near the trans-Golgi network (TGN). A brief treatment of Brefeldin A, which blocks vesicle budding from the Golgi, increased the amount of PICK1 and ICA69 at TGN. On the other hand, mature secretory granules were associated with PICK1 only, not ICA69. PICK1 deficiency in mice caused the complete loss of ICA69 and led to increased food and water intake but lower body weight. Glucose tolerance tests demonstrated that these mutant mice had high blood glucose, a consequence of insufficient insulin. Importantly, while the total insulin level was reduced in PICK1-deficient beta cells, proinsulin was increased. Lastly, ICA69 knockout mice also displayed similar phenotype as the mice deficient in PICK1. Together, our results indicate that PICK1 and ICA69 are key regulators of the formation and maturation of insulin granules.
authors: Division of Life Science, Division of Biomedical Engineering and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China.
authors: Mian
authors: M
authors: Cao
authors: Zhuo
authors: Z
authors: Mao
authors: Chuen
authors: C
authors: Kam
authors: Nan
authors: N
authors: Xiao
authors: Xiaoxing
authors: X
authors: Cao
authors: Chong
authors: C
authors: Shen
authors: Kenneth K Y
authors: KK
authors: Cheng
authors: Aimin
authors: A
authors: Xu
authors: Kwong-Man
authors: KM
authors: Lee
authors: Liwen
authors: L
authors: Jiang
authors: Jun
authors: J
authors: Xia
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000502:physiology*; D002352:Carrier Proteins / Q000502:physiology*; D018797:Cell Cycle Proteins; D002460:Cell Line; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000378:metabolism*; D007328:Insulin / Q000172:deficiency / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000502:physiology*; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D011384:Proinsulin / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D022142:Secretory Vesicles / Q000378:metabolism*
chemical_list: D001324:Autoantigens; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C490184:Ica1 protein, mouse; D007328:Insulin; D009687:Nuclear Proteins; C091822:Prkcabp protein, mouse; D011384:Proinsulin; D005947:Glucose
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