Proteasome inhibition alters glucose-stimulated (pro) insulin secretion and turnover in pancreatic β-cells

被引:66
作者
Kitiphongspattana, K
Mathews, CE
Leiter, EH
Gaskins, HR
机构
[1] Univ Illinois, Div Nutr Sci, Urbana, IL 61801 USA
[2] Univ Illinois, Dept Anim Sci, Urbana, IL 61801 USA
[3] Univ Illinois, Dept Vet Pathobiol, Urbana, IL 61801 USA
[4] Univ Illinois, Inst Genom Biol, Urbana, IL 61801 USA
[5] Univ Pittsburgh, Rangos Res Ctr, Inst Diabet, Pittsburgh, PA 15213 USA
[6] Jackson Lab, Bar Harbor, ME 04609 USA
关键词
D O I
10.1074/jbc.M410876200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 [生物化学与分子生物学]; 081704 [应用化学];
摘要
Metabolic labeling studies were conducted in freshly isolated mouse islets and a beta- cell line ( MIN6) to examine the effects of proteasome inhibition on glucose- stimulated ( pro) insulin synthesis and secretion. Glucose- stimulated ( pro) insulin synthesis, as determined by the incorporation of [ H-3] tyrosine, decreased significantly by 90% in islets and 71% in MIN6 cells pretreated with the proteasome inhibitor lactacystin ( 10 mu M) for 2 h. To follow the fate of newly synthesized ( pro) insulin, islets were pulse- labeled with [H-3] tyrosine ( 40 mu Ci) for 20 min and chased +/- lactacystin ( 10 mu M) for up to 4 h. The release of newly synthesized ( pro) insulin ([H-3] tyrosine-labeled) was similar between lactacystin- treated and control islets despite a 51% decrease ( p < 0.05) in total immunoreactive ( pro) insulin secretion by lactacystin-treated islets. The specific radioactivity of [H-3] tyrosine-labeled ( pro) insulin in the extracellular medium of lactacystin-treated islets ( 0.52 +/- 0.16 cpm/ microunits) was 2- fold greater relative to control islets ( 0.25 +/- 0.06 cpm/ microunits). Induction of the unfolded protein response by lactacystin, as evidenced by the up- regulation of endoplasmic reticulum ( ER) chaperones ( GRP78/ BiP, GRP94, protein disulfide isomerase) and induction of the stress- inducible transcription factor C/ EBP- homologous protein/ GADD153 ( CHOP/ GADD153), likely contributed to the release of newly synthesized ( pro) insulin to relieve ER stress. The present data indicate proteasome inhibition did not prevent, but increased ( p < 0.05), the intracellular degradation of [H-3] tyrosine- labeled ( pro) insulin from 8 to 24% in islets. Collectively, these data indicate beta- cells may balance glucose- stimulated ( pro) insulin synthesis and secretion with the activity of the proteasome to regulate protein concentrations in the ER.
引用
收藏
页码:15727 / 15734
页数:8
相关论文
共 68 条
[1]
The pathogenicity of islet-infiltrating lymphocytes in the non-obese diabetic (NOD) mouse [J].
Ablamunits, V ;
Elias, D ;
Cohen, IR .
CLINICAL AND EXPERIMENTAL IMMUNOLOGY, 1999, 115 (02) :260-267
[2]
Interferon-gamma independently activates the MHC class I antigen processing pathway and diminishes glucose responsiveness in pancreatic beta-cell lines [J].
Baldeon, ME ;
Neece, DJ ;
Nandi, D ;
Monaco, JJ ;
Gaskins, HR .
DIABETES, 1997, 46 (05) :770-778
[3]
Impairment of the ubiquitin-proteasome system by protein aggregation [J].
Bence, NF ;
Sampat, RM ;
Kopito, RR .
SCIENCE, 2001, 292 (5521) :1552-1555
[4]
Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response [J].
Bertolotti, A ;
Zhang, YH ;
Hendershot, LM ;
Harding, HP ;
Ron, D .
NATURE CELL BIOLOGY, 2000, 2 (06) :326-332
[5]
Role of Cue1p in ubiquitination and degradation at the ER surface [J].
Biederer, T ;
Volkwein, C ;
Sommer, T .
SCIENCE, 1997, 278 (5344) :1806-1809
[6]
The inhibition of microsomal triglyceride transfer protein activity in rat hepatoma cells promotes proteasomal and nonproteasomal degradation of apoprotein B100 [J].
Cardozo, C ;
Wu, XY ;
Pan, MH ;
Wang, HX ;
Fisher, EA .
BIOCHEMISTRY, 2002, 41 (31) :10105-10114
[7]
A MUTANT HUMAN PROINSULIN IS SECRETED FROM ISLETS OF LANGERHANS IN INCREASED AMOUNTS VIA AN UNREGULATED PATHWAY [J].
CARROLL, RJ ;
HAMMER, RE ;
CHAN, SJ ;
SWIFT, HH ;
RUBENSTEIN, AH ;
STEINER, DF .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1988, 85 (23) :8943-8947
[8]
Dissociation from BiP and retrotranslocation of unassembled immunoglobulin light chains are tightly coupled to proteasome activity [J].
Chillarón, J ;
Haas, IG .
MOLECULAR BIOLOGY OF THE CELL, 2000, 11 (01) :217-226
[9]
Ubiquitination is required for the retro-translocation of a short-lived luminal endoplasmic reticulum glycoprotein to the cytosol for degradation by the proteasome [J].
de Virgilio, M ;
Weninger, H ;
Ivessa, NE .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (16) :9734-9743
[10]
Setting the standards: Quality control in the secretory pathway [J].
Ellgaard, L ;
Molinari, M ;
Helenius, A .
SCIENCE, 1999, 286 (5446) :1882-1888