A novel role for the centrosomal protein, pericentrin, in regulation of insulin secretory vesicle docking in mouse pancreatic beta-cells.
The centrosome is important for microtubule organization and cell cycle progression in animal cells. Recently, mutations in the centrosomal protein, pericentrin, have been linked to human microcephalic osteodysplastic primordial dwarfism (MOPD II), a rare genetic disease characterized by severe growth retardation and early onset of type 2 diabetes among other clinical manifestations. While the link between centrosomal and cell cycle defects may account for growth deficiencies, the mechanism linking pericentrin mutations with dysregulated glucose homeostasis and pre-pubertal onset of diabetes is unknown. In this report we observed abundant expression of pericentrin in quiescent pancreatic beta-cells of normal animals which led us to hypothesize that pericentrin may have a critical function in beta-cells distinct from its known role in regulating cell cycle progression. In addition to the typical centrosome localization, pericentrin was also enriched with secretory vesicles in the cytoplasm. Pericentrin overexpression in beta-cells resulted in aggregation of insulin-containing secretory vesicles with cytoplasmic, but not centrosomal, pericentriolar material and an increase in total levels of intracellular insulin. RNAi- mediated silencing of pericentrin in secretory beta-cells caused dysregulated secretory vesicle hypersecretion of insulin into the media. Together, these data suggest that pericentrin may regulate the intracellular distribution and secretion of insulin. Mice transplanted with pericentrin-depleted islets exhibited abnormal fasting hypoglycemia and inability to regulate blood glucose normally during a glucose challenge, which is consistent with our in vitro data. This previously unrecognized function for a centrosomal protein to mediate vesicle docking in secretory endocrine cells emphasizes the adaptability of these scaffolding proteins to regulate diverse cellular processes and identifies a novel target for modulating regulated protein secretion in disorders such as diabetes.
Jurczyk
Agata
A
Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
Pino
Steven C
SC
O'Sullivan-Murphy
Bryan
B
Addorio
Martha
M
Lidstone
Erich A
EA
Diiorio
Philip
P
Lipson
Kathryn L
KL
Standley
Clive
C
Fogarty
Kevin
K
Lifshitz
Lawrence
L
Urano
Fumihiko
F
Mordes
John P
JP
Greiner
Dale L
DL
Rossini
Aldo A
AA
Bortell
Rita
R
D000818:Animals; D000941:Antigens / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D018385:Centrosome / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D046529:Microscopy, Electron, Transmission; D034741:RNA, Small Interfering / Q000235:genetics; D011863:Radioimmunoassay; D022142:Secretory Vesicles / Q000378:metabolism* / Q000648:ultrastructure
D000941:Antigens; D007328:Insulin; D034741:RNA, Small Interfering; C086178:pericentrin