Cyclic AMP signaling stimulates proteasome degradation of thioredoxin interacting protein (TxNIP) in pancreatic β-cells
Cyclic AMP signaling stimulates proteasome degradation of thioredoxin interacting protein (TxNIP) in pancreatic β-cells
复制标题
DOI：
10.1016/j.cellsig.2010.04.001
复制
发表时间：
2010-08-01
影响因子：
4.8
通讯作者：
Jin, Tianru
中科院分区：
文献类型：
--
作者：
Shao, Weijuan;Yu, Zhiwen;Jin, Tianru
硫氧还蛋白相互作用蛋白（TxNIP）在胰腺β细胞中发挥糖毒性效应。Exendin-4 （Ex-4）是一种长期有效的GLP-1受体激动剂，可降低胰腺β细胞中的TxNIP水平。然而，这种减少的机制在很大程度上仍然未知。我们在这里发现，ex - 4,8 -溴-cAMP、cAMP促进剂forskolin、蛋白激酶A激活剂（PKA）和cAMP激活的交换蛋白（Epac）都能减弱高糖（20 mM）对胰腺β细胞系Ins-1中TxNIP水平的影响。Forskolin和Ex-4也能降低培养的原代大鼠胰岛的TxNIP水平。这种抑制作用至少部分是通过刺激蛋白酶体依赖性的TxNIP降解来介导的，因为蛋白酶体抑制剂MG132（而不是溶酶体抑制剂chloroquine）可以显著阻断forskolin的抑制作用。此外，福斯克林增强TxNIP泛素化。PKA抑制和Epac抑制均部分阻断了福斯克林对TxNIP水平的抑制作用。此外，通过测量caspase 3活性，forskolin和Ex-4可以保护Ins-1细胞免受高糖诱导的凋亡活性的影响。最后，敲低TxNIP表达导致caspase 3表达水平降低，对forskolin治疗的反应减弱。我们认为蛋白酶体依赖性的TxNIP降解是Ex-4-cAMP信号传导保护胰腺细胞的一种新机制。(C) 2010爱思唯尔公司版权所有。
Thioredoxin interacting protein (TxNIP) functions as an effector of glucotoxicity in pancreatic beta-cells. Exendin-4 (Ex-4), a long-term effective GLP-1 receptor agonist, reduces TxNIP level in pancreatic beta-cells. Mechanisms underlying this reduction, however, remain largely unknown. We show here that Ex-4, 8-bromo-cAMP, the cAMP promoting agent forskolin, as well as activators of protein kinase A (PKA) and exchange protein activated by cAMP (Epac), all attenuated the effect of high glucose (20 mM) on TxNIP level in the pancreatic beta-cell line Ins-1. Forskolin and Ex-4 also reduced TxNIP level in cultured primary rat islets. This repressive effect is at least partially mediated via stimulating proteasome-dependent TxNIP degradation, since the proteasomal inhibitor MG132, but not the lysosomal inhibitor chloroquine, significantly blocked the repressive effect of forskolin. Furthermore, forskolin enhanced TxNIP ubiquitination. Both PKA inhibition and Epac inhibition partially blocked the repressive effect of forskolin on TxNIP level. In addition, forskolin and Ex-4 protected Ins-1 cells from high glucose-induced apoptotic activity, assessed by measuring caspase 3 activity. Finally, knockdown of TxNIP expression led to reduced caspase 3 expression levels and blunted response to forskolin treatment. We suggest that proteasome-dependent TxNIP degradation is a novel mechanism by which Ex-4-cAMP signaling protects pancreatic beta cells. (C) 2010 Elsevier Inc. All rights reserved.