PICK1 deficiency impairs secretory vesicle biogenesis and leads to growth retardation and decreased glucose tolerance
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
PICK1 deficiency impairs secretory vesicle biogenesis and leads to growth retardation and decreased glucose tolerance. / Holst, Birgitte; Madsen, Kenneth L; Jansen, Anna M; Jin, Chunyu; Rickhag, Karl Mattias; Lund, Viktor K; Jensen, Morten; Bhatia, Vikram; Sørensen, Gunnar; Madsen, Andreas N; Xue, Zhichao; Møller, Siri K; Woldbye, David; Qvortrup, Klaus; Huganir, Richard; Stamou, Dimitrios; Kjærulff, Ole; Gether, Ulrik.
In: P L o S Biology (Online), Vol. 11, No. 4, e1001542, 04.2013, p. 1-25.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - PICK1 deficiency impairs secretory vesicle biogenesis and leads to growth retardation and decreased glucose tolerance
AU - Holst, Birgitte
AU - Madsen, Kenneth L
AU - Jansen, Anna M
AU - Jin, Chunyu
AU - Rickhag, Karl Mattias
AU - Lund, Viktor K
AU - Jensen, Morten
AU - Bhatia, Vikram
AU - Sørensen, Gunnar
AU - Madsen, Andreas N
AU - Xue, Zhichao
AU - Møller, Siri K
AU - Woldbye, David
AU - Qvortrup, Klaus
AU - Huganir, Richard
AU - Stamou, Dimitrios
AU - Kjærulff, Ole
AU - Gether, Ulrik
PY - 2013/4
Y1 - 2013/4
N2 - 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.
AB - 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.
U2 - 10.1371/journal.pbio.1001542
DO - 10.1371/journal.pbio.1001542
M3 - Journal article
C2 - 23630454
VL - 11
SP - 1
EP - 25
JO - PLoS Biology
JF - PLoS Biology
SN - 1544-9173
IS - 4
M1 - e1001542
ER -
ID: 45527701