XBP1-FoxO1 interaction regulates ER stress-induced autophagy in auditory cells.
XBP1-FoxO1 interaction regulates ER stress-induced autophagy in auditory cells.
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DOI：
10.1038/s41598-017-02960-1
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发表时间：
2017-06-30
影响因子：
4.6
通讯作者：
Oshima T
中科院分区：
文献类型：
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作者：
Kishino A;Hayashi K;Hidai C;Masuda T;Nomura Y;Oshima T
本研究旨在探讨内质网应激下听细胞中X-box结合蛋白1（X-box binding protein 1 unspliced，spliced，XBP 1u，s）、叉头盒O 1（Forkhead box O 1，FoxO 1）与自噬的关系。此外，还研究了引起未折叠蛋白反应（UPR）的ER应激与自噬之间的关系。本研究报道了衣霉素处理的ER应激诱导，导致IRE 1 α介导的XBP 1 mRNA剪接和自噬。研究发现XBP 1 mRNA剪接和FoxO 1参与ER应激诱导的自噬。这一推断是基于观察到LC 3-II的表达被IRE 1 α、XBP 1或FoxO 1的敲低所抑制。此外，在ER应激下，发现XBP 1u与听觉细胞中的XBP 1 s相互作用，作为负反馈调节剂发挥作用，这是基于两个重要的发现。结果表明，在大肠杆菌中，XBP 1u和XBP 1 s的表达呈显著负相关; XBP 1蛋白的表达与XBP 1 mRNA的表达呈不同的动态变化。此外，我们的研究结果之间的关系，XBP 1和FoxO 1的小干扰RNA（siRNA）矛盾地显示负调控FoxO 1的表达XBP 1。我们的研究结果表明，XBP 1-FoxO 1相互作用调节ER应激诱导的听觉细胞自噬。
The purpose of this study was to clarify the relationship among X-box-binding protein 1 unspliced, spliced (XBP1u, s), Forkhead box O1 (FoxO1) and autophagy in the auditory cells under endoplasmic reticulum (ER) stress. In addition, the relationship between ER stress that causes unfolded protein response (UPR) and autophagy was also investigated. The present study reported ER stress induction by tunicamycin treatment that resulted in IRE1α-mediated XBP1 mRNA splicing and autophagy. XBP1 mRNA splicing and FoxO1 were found to be involved in ER stress-induced autophagy. This inference was based on the observation that the expression of LC3-II was suppressed by knockdown of IRE1α, XBP1 or FoxO1. In addition, XBP1u was found to interact with XBP1s in auditory cells under ER stress, functioning as a negative feedback regulator that was based on two important findings. Firstly, there was a significant inverse correlation between XBP1u and XBP1s expressions, and secondly, the expression of XBP1 protein showed different dynamics compared to the XBP1 mRNA level. Furthermore, our results regarding the relationship between XBP1 and FoxO1 by small interfering RNA (siRNA) paradoxically showed negative regulation of FoxO1 expression by XBP1. Our findings revealed that the XBP1-FoxO1 interaction regulated the ER stress-induced autophagy in auditory cells.