a Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, P. R. China.
b University of Science and Technology of China, Hefei 230026, Anhui, China.
Radiat Res. 2018 Nov;190(5):494-503. doi: 10.1667/RR15073.1. Epub 2018 Aug 10.
Connexin molecules are an important component of the gap junction, with connexin43 (Cx43) being the most abundantly expressed type. Src is a nonreceptor tyrosine-protein kinase that affects Cx43 activity by multiple mechanisms. However, it is not clear how Src regulates Cx43 to influence radiation-induced bystander effects (RIBEs). In this study, we demonstrated that Cx43 on Tyr265 was phosphorylated by activated Src in α-irradiated HepG2 cells, with the total expression of Cx43 unchanged. After inhibition of Cx43 phosphorylation in irradiated cells, the frequency of γ-H2AX foci formation in adjacent nonirradiated bystander cells was significantly enhanced. Furthermore, this study showed that autophagy regulated the activity of Src and phosphorylation of Cx43, and the level of autophagy was correlated with the radiation-induced reactive oxygen species (ROS). These results suggest that ROS and autophagy play an important role in regulating the Src-Cx43 axis to affect the RIBEs. Our findings provide new insights into the Cx43-mediated gap junction intercellular communication, as well as the underlying mechanism of RIBEs.
连接子分子是间隙连接的重要组成部分，其中连接蛋白 43（Cx43）表达最为丰富。Src 是一种非受体酪氨酸蛋白激酶，通过多种机制影响 Cx43 的活性。然而，Src 如何调节 Cx43 以影响辐射诱导的旁观者效应（RIBEs）尚不清楚。在这项研究中，我们证明了在α辐照的 HepG2 细胞中，激活的 Src 使 Cx43 的 Tyr265 磷酸化，而 Cx43 的总表达不变。在抑制辐照细胞中 Cx43 的磷酸化后，相邻未辐照旁观者细胞中 γ-H2AX 焦点形成的频率显著增加。此外，本研究表明自噬调节 Src 和 Cx43 的磷酸化，自噬水平与辐射诱导的活性氧（ROS）有关。这些结果表明，ROS 和自噬在调节 Src-Cx43 轴以影响 RIBEs 中起着重要作用。我们的研究结果为 Cx43 介导的间隙连接细胞间通讯以及 RIBEs 的潜在机制提供了新的见解。
