Thioredoxin-interacting protein mediates nuclear-to-plasma membrane communication: role in vascular endothelial growth factor 2 signaling.
Thioredoxin-interacting protein mediates nuclear-to-plasma membrane communication: role in vascular endothelial growth factor 2 signaling.
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DOI：
10.1161/atvbaha.111.244681
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发表时间：
2012-05
期刊：
影响因子：
--
通讯作者：
Berk BC
中科院分区：
文献类型：
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作者：
Spindel ON;Yan C;Berk BC
在人脐静脉内皮细胞（HUVEC）中，硫氧还蛋白相互作用蛋白（TXNIP）和多adp核糖聚合酶1 （PARP1）均受细胞还原-氧化（氧化还原）状态变化的调控，并基本定位于细胞核。之前，我们发现了一种新的机制，通过激活血管内皮生长因子受体2 （VEGFR2）信号来响应应激诱导的细胞凋亡，从而抑制PARP1介导的HUVEC存活。此外，我们发现TXNIP易位到质膜（PM），并在生理刺激下激活VEGFR2。由于TXNIP是一种调节VEGFR2信号的α-抑制蛋白，我们假设PARP1调节TXNIP的定位和功能可能影响HUVEC应激诱导的凋亡。用10µmol/L PARP1抑制剂（PJ34）处理的HUVEC可以免受TNF （10 ng/mL）或H2O2（300µmol/L）介导的细胞死亡。转染TXNIP siRNA的HUVEC失去了PARP1抑制的保护作用，提示TXNIP具有保护作用。通过免疫荧光、细胞分离分析和质膜薄片分析，TXNIP被证明在PARP1抑制后会转移到质膜上。TXNIP易位与VEGFR2信号的激活有关。功能上，PJ34处理降低了TXNIP与PARP1的相互作用，提示PARP1是TXNIP定位和功能的新调节剂。这些发现证明了PARP1介导TXNIP激活质膜信号和细胞存活的新调控机制。
Thioredoxin-interacting protein (TXNIP) and poly-ADP-ribose polymerase 1 (PARP1) are both regulated by changes in cellular reduction-oxidation (redox) state and localize to the nucleus basally in human umbilical vein endothelial cells (HUVEC). Previously we showed a novel mechanism for PARP1 inhibition–mediated HUVEC survival through activation of vascular endothelial growth factor receptor 2 (VEGFR2) signaling in response to stress-induced apoptosis. In addition, we showed TXNIP translocation to the plasma membrane (PM) and activation of VEGFR2 in response to physiological stimuli. Because TXNIP is an α-arrestin that regulates VEGFR2 signaling, we hypothesized that PARP1 regulates TXNIP localization and function that might affect HUVEC stress-induced apoptosis. HUVEC treated with 10 µmol/L PARP1 inhibitor (PJ34) were protected from TNF (10 ng/mL) or H2O2 (300 µmol/L) mediated cell death. HUVEC transfected with TXNIP siRNA lost the protective effect of PARP1 inhibition, suggesting a protective role for TXNIP. Using immunofluorescence, cell fractionation analysis, and plasma membrane sheet assay, TXNIP was shown to translocate to the plasma membrane after PARP1 inhibition. TXNIP translocation was associated with activation of VEGFR2 signaling. Functionally, TXNIP-PARP1 interaction was decreased on PJ34 treatment, suggesting PARP1 as a novel regulator of TXNIP localization and function. These findings demonstrate a novel regulatory mechanism of TXNIP by PARP1 to mediate activation of plasma membrane signaling and cell survival.