14-3-3θ facilitates plasma membrane delivery and function of mechanosensitive connexin 43 hemichannels
14-3-3θ facilitates plasma membrane delivery and function of mechanosensitive connexin 43 hemichannels
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DOI：
10.1242/jcs.133553
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发表时间：
2014-01-01
影响因子：
4
通讯作者：
Jiang, Jean X.
中科院分区：
文献类型：
--
作者：
Batra, Nidhi;Riquelme, Manuel A.;Jiang, Jean X.
机械负荷激活的骨细胞内的细胞内信号传导对于骨形成和重塑很重要。这些信号事件由 Cx43 半通道 (HC) 释放的小调节剂介导。我们最近发现整合素α5能够感知机械刺激并诱导Cx43 HC的开放；然而，其根本机制尚不清楚。在这里，我们表明 Cx43 和整合素 α 5 都与 14-3-3 theta 相互作用，并且这种相互作用是 Cx43 HC 在机械应力下打开所必需的。 14-3-3 theta 的缺失阻止了 Cx43 和整合素 α 5 之间的相互作用，并阻止了 HC 的开放。此外，它还减少了 Cx43 和整合素 α 5 从高尔基体到质膜的转运。机械负荷促进 Cx43 向表面的移动，这不仅与 14-3-3 theta 水平的增加有关，而且还与 Cx43 和整合素 α 5 的相互作用有关。机械负荷对向前运输的这种刺激作用在没有 14-3-3 theta 的情况下减弱，并且大部分 Cx43 在高尔基体中积累。布雷菲德菌素 A 对高尔基体的破坏减少了 Cx43 和整合素 α 5 与 14-3-3 theta 的关联，进一步表明这种相互作用可能发生在高尔基体中。总之，这些结果定义了 14-3-3 theta 在协助将 Cx43 和整合素 α 5 递送至质膜以在骨细胞中形成机械敏感性 HC 方面的先前未识别的支架作用。
Intracellular signaling in osteocytes activated by mechanical loading is important for bone formation and remodeling. These signaling events are mediated by small modulators released from Cx43 hemichannels (HC). We have recently shown that integrin alpha 5 senses the mechanical stimulation and induces the opening of Cx43 HC; however, the underlying mechanism is unknown. Here, we show that both Cx43 and integrin alpha 5 interact with 14-3-3 theta, and this interaction is required for the opening of Cx43 HC upon mechanical stress. The absence of 14-3-3 theta prevented the interaction between Cx43 and integrin alpha 5, and blocked HC opening. Furthermore, it decreased the transport of Cx43 and integrin alpha 5 from the Golgi apparatus to the plasma membrane. Mechanical loading promoted the movement of Cx43 to the surface which was associated not only with an increase in 14-3-3 theta levels but also its interaction with Cx43 and integrin alpha 5. This stimulatory effect on forward transport by mechanical loading was attenuated in the absence of 14-3-3 theta and the majority of the Cx43 accumulated in the Golgi. Disruption of the Golgi by brefeldin A reduced the association of Cx43 and integrin alpha 5 with 14-3-3 theta, further suggesting that the interaction is likely to occur in the Golgi. Together, these results define a previously unidentified, scaffolding role of 14-3-3 theta in assisting the delivery of Cx43 and integrin alpha 5 to the plasma membrane for the formation of mechanosensitive HC in osteocytes.