Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China; Division of Molecular Signaling, Department of the Advanced Biomedical Research, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
Division of Molecular Signaling, Department of the Advanced Biomedical Research, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
Cell Signal. 2017 Oct;38:116-126. doi: 10.1016/j.cellsig.2017.07.001. Epub 2017 Jul 8.
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 Glut1 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.
间隙连接 (GJ) 在控制细胞结构、功能和代谢方面发挥着重要作用。然而，其涉及的分子机制仍知之甚少。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 抑制剂或间隙连接蛋白 43 (Cx43) siRNA 破坏 GJ 可强烈抑制 TXNIP，这伴随着细胞外信号调节激酶 (ERK) 的激活。用化学抑制剂抑制 ERK 或其上游激酶可阻止 TXNIP 的减少。相反，用有丝分裂原或磷酸酶抑制剂激活 ERK 可再现 GJ 的抑制作用。进一步的分析表明，GJ 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效果。此外，抑制 GJ 以类似于 TXNIP 下调的方式增加 Glut1 并增强细胞对 ER 应激的抵抗力。总之，我们的研究因此将 ERK 介导的 TXNIP 抑制描述为 GJ 调节细胞行为的一种未被报道的机制。
