Role of furin in granular acidification in the endocrine pancreas: Identification of the V-ATPase subunit Ac45 as a candidate substrate

被引:67
作者
Louagie, Els [1 ]
Taylor, Neil A. [1 ,3 ]
Flamez, Daisy [4 ]
Roebroek, Anton J. M. [1 ]
Bright, Nicholas A. [5 ]
Meulemans, Sandra [1 ]
Quintens, Roel [2 ]
Herrera, Pedro L. [6 ]
Schuit, Frans [2 ]
Van de Ven, Wim J. M. [1 ]
Creemers, John W. M. [1 ]
机构
[1] Katholieke Univ Leuven, Dept Human Genet, B-3000 Louvain, Belgium
[2] Katholieke Univ Leuven, Dept Mol & Cell Biol, B-3000 Louvain, Belgium
[3] Li Ka Shing Ctr, Cambridge Res Inst, Canc Res UK, Cambridge CB2 0RE, England
[4] Univ Libre Bruxelles, Expt Med Lab, B-1070 Brussels, Belgium
[5] Univ Cambridge, Addenbrookes Hosp, Cambridge Inst Med Res, Cambridge EB2 0XY, England
[6] Univ Geneva, Fac Med, Dept Genet Med & Dev, CH-1211 Geneva 4, Switzerland
基金
英国医学研究理事会;
关键词
endoprotease; insulin; islets of Langerhans; proton pump; proprotein convertase;
D O I
10.1073/pnas.0800340105
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Furin is a proprotein convertase which activates a variety of regulatory proteins in the constitutive exocytic and endocytic pathway. The effect of genetic ablation of fur was studied in the endocrine pancreas to define its physiological function in the regulated secretory pathway. Pdx1-Cre/loxP furin KO mice show decreased secretion of insulin and impaired processing of known PC2 substrates like proPC2 and proinsulin Ill. Both secretion and PC2 activity depend on granule acidification, which was demonstrated to be significantly decreased in furin-deficient beta cells by using the acidotrophic agent 3-(2,4-dinitroanilino)-3'amino-N-methyidipropylamine (DAMP). Ac45, an accessory subunit of the proton pump V-ATPase, was investigated as a candidate substrate. Ac45 is highly expressed in islets of Langerhans and furin was able to cleave Ac45 ex vivo. Furthermore, the exact cleavage site was determined. In addition, reduced regulated secretion and proinsulin II processing could be obtained in the insulinoma cell line beta TC3 by downregulation of either furin or Ac45. Together, these data establish an important role for furin in regulated secretion, particularly in intragranular acidification most likely due to impaired processing of Ac45.
引用
收藏
页码:12319 / 12324
页数:6
相关论文
共 49 条
[1]  
Barg S, 2001, J CELL SCI, V114, P2145
[2]   Neuropeptides of the islets of Langerhans: A peptidomics study [J].
Boonen, Kurt ;
Baggerman, Geert ;
Hertog, Wannes D' ;
Husson, Steven J. ;
Overbergh, Lut ;
Mathieu, Chantal ;
Schoofs, Liliane .
GENERAL AND COMPARATIVE ENDOCRINOLOGY, 2007, 152 (2-3) :231-241
[3]   Carboxypeptidase E is a regulated secretory pathway sorting receptor: Genetic obliteration leads to endocrine disorders in Cpe(fat) mice [J].
Cool, DR ;
Normant, E ;
Shen, FS ;
Chen, HC ;
Pannell, L ;
Zhang, Y ;
Loh, YP .
CELL, 1997, 88 (01) :73-83
[4]   Binding of BiP to the processing enzyme lymphoma proprotein convertase prevents aggregation, but slows down maturation [J].
Creemers, JWM ;
van de Loo, JWHP ;
Plets, E ;
Hendershot, LM ;
Van de Ven, WJM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (49) :38842-38847
[5]   Identification of a transferable sorting domain for the regulated pathway in the prohormone convertase PC2 [J].
Creemers, JWM ;
Usac, EF ;
Bright, NA ;
VandeLoo, JW ;
Jansen, E ;
VandeVen, WJM ;
Hutton, JC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (41) :25284-25291
[6]   Agouti-related protein is posttranslationally cleaved by proprotein convertase 1 to generate agouti-related protein (AGRP)83-132:: Interaction between AGRP83-132 and melanocortin receptors cannot be influenced by syndecan-3 [J].
Creemers, JWM ;
Pritchard, LE ;
Gyte, A ;
Le Rouzic, P ;
Meulemans, S ;
Wardlaw, SL ;
Zhu, XR ;
Steiner, DF ;
Davies, N ;
Armstrong, D ;
Lawrence, CB ;
Luckman, SM ;
Schmitz, CA ;
Davies, RA ;
Brennand, JC ;
White, A .
ENDOCRINOLOGY, 2006, 147 (04) :1621-1631
[7]   THE INSULIN-SECRETORY-GRANULE CARBOXYPEPTIDASE-H - PURIFICATION AND DEMONSTRATION OF INVOLVEMENT IN PROINSULIN PROCESSING [J].
DAVIDSON, HW ;
HUTTON, JC .
BIOCHEMICAL JOURNAL, 1987, 245 (02) :575-582
[8]   INTRAORGANELLAR CALCIUM AND PH CONTROL PROINSULIN CLEAVAGE IN THE PANCREATIC BETA-CELL VIA 2 DISTINCT SITE-SPECIFIC ENDOPEPTIDASES [J].
DAVIDSON, HW ;
RHODES, CJ ;
HUTTON, JC .
NATURE, 1988, 333 (6168) :93-96
[9]   Interaction of furin in immature secretory granules from neuroendocrine cells with the AP-1 adaptor complex is modulated by casein kinase II phosphorylation [J].
Dittie, AS ;
Thomas, L ;
Thomas, G ;
Tooze, SA .
EMBO JOURNAL, 1997, 16 (16) :4859-4870
[10]   Mouse pancreatic β-cells exhibit preserved glucose competence after disruption of the glucagon-like peptide-1 receptor gene [J].
Flamez, D ;
Van Breusegem, A ;
Scrocchi, LA ;
Quartier, E ;
Pipeleers, D ;
Drucker, DJ ;
Schuit, F .
DIABETES, 1998, 47 (04) :646-652