The pivotal role of extracellular signal-regulated kinase in gap junction mediated regulation of TXNIP
The pivotal role of extracellular signal-regulated kinase in gap junction mediated regulation of TXNIP
复制标题
细胞外信号调节激酶在间隙连接介导的 TXNIP 调节中的关键作用
DOI：
10.1016/j.cellsig.2017.07.001
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发表时间：
2017-10-01
影响因子：
4.8
通讯作者：
Yao, Jian
中科院分区：
文献类型：
--
作者：
Gao, Shan;Zhang, Xiling;Yao, Jian
间隙连接（GJ）在细胞结构、功能和代谢的控制中发挥着重要作用。然而，所涉及的分子机制仍然知之甚少。鉴于硫氧还蛋白相互作用蛋白 (TXNIP) 调节广泛的细胞过程，我们测试了 TXNIP 可能的参与。用几种化学 GJ 抑制剂或 connexin43 (Cx43) siRNA 破坏 GJ 可以有效抑制 TXNIP，随后激活细胞外信号调节激酶 (ERK)。用化学抑制剂抑制 ERK 或其上游激酶可阻止 TXNIP 的还原。相反，用有丝分裂原或磷酸酶抑制剂激活 ERK 会再现 GJ 的抑制作用。进一步的分析表明，GJs的功能障碍促进了TXNIP的磷酸化、泛素化和降解，而ERK的抑制则产生相反的作用。此外，抑制 GJ 会提高 Glut1 并增强细胞对 ER 应激的抵抗力，其方式与 TXNIP 下调类似。总的来说，我们的研究将 ERK 介导的 TXNIP 抑制描述为一种目前尚未报道的 GJ 调节细胞行为的机制。
Gap junctions (GJs) play a major role in the control of cell structure, function, and metabolism. However, the molecular mechanisms involved are still poorly understood. Given that thioredoxin-interacting protein (TXNIP) regulates a broad range of cellular processes, we tested the possible involvement of TXNIP. Disruption of GJs with several chemical GJ inhibitors or connexin43 (Cx43) siRNA potently suppressed TXNIP, which was preceded by an activation of extracellular signal-regulated kinase (ERK). Inhibition of ERK or its upstream kinase with chemical inhibitors prevented the reduction of TXNIP. On the contrary, activation of ERK with mitogens or phosphatase inhibitors reproduced the suppressive effects of GJs. Further analysis revealed that dysfunction of GJs promoted TXNIP phosphorylation, ubiquitination, and degradation, whereas inhibition of ERK exerted the opposite effects. Moreover, inhibition of GJs elevated Glutl and enhanced cell resistance to ER stress in a similar way to TXNIP downregulation. Collectively, our study thus characterizes ERK-mediated suppression of TXNIP as a presently unreported mechanism by which GJs regulate cell behaviors.