title: PICK1 deficiency impairs secretory vesicle biogenesis and leads to growth retardation and decreased glucose tolerance.
abstract: Secretory vesicles in endocrine cells store hormones such as growth hormone (GH) and insulin before their release into the bloodstream. The molecular mechanisms governing budding of immature secretory vesicles from the trans-Golgi network (TGN) and their subsequent maturation remain unclear. Here, we identify the lipid binding BAR (Bin/amphiphysin/Rvs) domain protein PICK1 (protein interacting with C kinase 1) as a key component early in the biogenesis of secretory vesicles in GH-producing cells. Both PICK1-deficient Drosophila and mice displayed somatic growth retardation. Growth retardation was rescued in flies by reintroducing PICK1 in neurosecretory cells producing somatotropic peptides. PICK1-deficient mice were characterized by decreased body weight and length, increased fat accumulation, impaired GH secretion, and decreased storage of GH in the pituitary. Decreased GH storage was supported by electron microscopy showing prominent reduction in secretory vesicle number. Evidence was also obtained for impaired insulin secretion associated with decreased glucose tolerance. PICK1 localized in cells to immature secretory vesicles, and the PICK1 BAR domain was shown by live imaging to associate with vesicles budding from the TGN and to possess membrane-sculpting properties in vitro. In mouse pituitary, PICK1 co-localized with the BAR domain protein ICA69, and PICK1 deficiency abolished ICA69 protein expression. In the Drosophila brain, PICK1 and ICA69 co-immunoprecipitated and showed mutually dependent expression. Finally, both in a Drosophila model of type 2 diabetes and in high-fat-diet-induced obese mice, we observed up-regulation of PICK1 mRNA expression. Our findings suggest that PICK1, together with ICA69, is critical during budding of immature secretory vesicles from the TGN and thus for vesicular storage of GH and possibly other hormones. The data link two BAR domain proteins to membrane remodeling processes in the secretory pathway of peptidergic endocrine cells and support an important role of PICK1/ICA69 in maintenance of metabolic homeostasis.
authors: Laboratory for Molecular Pharmacology, Novo Nordisk Foundation Center for Basic Metabolic Research, The Faculty of Health Sciences, Panum Institute, University of Copenhagen, Copenhagen, Denmark. holst@sund.ku.dk
authors: Birgitte
authors: B
authors: Holst
authors: Kenneth L
authors: KL
authors: Madsen
authors: Anna M
authors: AM
authors: Jansen
authors: Chunyu
authors: C
authors: Jin
authors: Mattias
authors: M
authors: Rickhag
authors: Viktor K
authors: VK
authors: Lund
authors: Morten
authors: M
authors: Jensen
authors: Vikram
authors: V
authors: Bhatia
authors: Gunnar
authors: G
authors: Sørensen
authors: Andreas N
authors: AN
authors: Madsen
authors: Zhichao
authors: Z
authors: Xue
authors: Siri K
authors: SK
authors: Møller
authors: David
authors: D
authors: Woldbye
authors: Klaus
authors: K
authors: Qvortrup
authors: Richard
authors: R
authors: Huganir
authors: Dimitrios
authors: D
authors: Stamou
authors: Ole
authors: O
authors: Kjærulff
authors: Ulrik
authors: U
authors: Gether
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000502:physiology; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics; D018797:Cell Cycle Proteins; D002460:Cell Line; D002522:Chlorocebus aethiops; D004331:Drosophila melanogaster; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism*; D006130:Growth Disorders / Q000235:genetics / Q000378:metabolism*; D013006:Growth Hormone / Q000172:deficiency / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D010902:Pituitary Gland / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D022142:Secretory Vesicles / Q000378:metabolism*; D059008:Time-Lapse Imaging; D021601:trans-Golgi Network / 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; D013006:Growth Hormone; D005947:Glucose
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