Department of Cell Biology and Genetics, Core Facility of Development Biology, Chongqing Medical University, Chongqing 400016, China.
Cell Signal. 2013 Nov;25(11):2136-46. doi: 10.1016/j.cellsig.2013.06.011. Epub 2013 Jun 29.
Bone morphogenetic protein 2 is known to activate unfolded protein response signaling molecules, including XBP1S, BiP and IRE1α. Endoplasmic reticulum stress is induced in chondrogenesis and activates IRE1α signal pathway, which is associated with ER stress-mediated apoptosis. However, the influence on IRE1α and BiP in BMP2-induced chondrocyte differentiation has not yet been elucidated; the molecular mechanism remains unexplored. In this study, we demonstrate that IRE1α interacts with BiP in unstressed cells and dissociates from BiP in the course of cartilage development. Induction of ER stress-responsive proteins (XBP1S, IRE1α, BiP) was also observed in differentiating cells. IRE1α inhibition ER stress-mediated apoptosis lies in the process of chondrocyte differentiation. Furthermore, knockdown of IRE1α expression by way of the RNAi approach accelerates ER stress-mediated apoptosis in chondrocyte differentiation induced by BMP2, as revealed by enhanced expressions of cleaved caspase3, CHOP and p-JNK1; and this IRE1α inhibition effect on ER stress-mediated apoptosis is required for BiP in chondrogenesis. Collectively, the ER stress sensors were activated during apoptosis in cartilage development, suggesting that selective activation of ER stress signaling was sufficient for induction of apoptosis. These findings reveal a novel critical role of IRE1α in ER stress-mediated apoptosis and the molecular mechanisms involved. These results suggest that activation of p-JNK1, caspase3 and CHOP was detected in developing chondrocytes and that specific ER stress signaling leads to naturally occurring apoptosis during cartilage development.
骨形态发生蛋白 2 已知可激活未折叠蛋白反应信号分子，包括 XBP1S、BiP 和 IRE1α。软骨形成过程中会诱导内质网应激，并激活 IRE1α 信号通路，这与 ER 应激介导的细胞凋亡有关。然而，BMP2 诱导的软骨细胞分化中 IRE1α 和 BiP 的影响尚未阐明；分子机制仍未得到探索。在这项研究中，我们证明 IRE1α 在未受应激的细胞中与 BiP 相互作用，并在软骨发育过程中从 BiP 中解离。还观察到分化细胞中内质网应激反应蛋白（XBP1S、IRE1α、BiP）的诱导。IRE1α 抑制 ER 应激介导的细胞凋亡发生在软骨细胞分化过程中。此外，通过 RNAi 方法敲低 IRE1α 表达会加速 BMP2 诱导的软骨细胞分化中 ER 应激介导的细胞凋亡，这表现为 cleaved caspase3、CHOP 和 p-JNK1 的表达增强；IRE1α 抑制 ER 应激介导的细胞凋亡需要 BiP 在软骨发生中起作用。总之，内质网应激传感器在软骨发育过程中的细胞凋亡中被激活，这表明选择性激活内质网应激信号足以诱导细胞凋亡。这些发现揭示了 IRE1α 在 ER 应激介导的细胞凋亡中的新的关键作用及其涉及的分子机制。这些结果表明，p-JNK1、caspase3 和 CHOP 在发育中的软骨细胞中被检测到，并且特定的内质网应激信号导致软骨发育过程中的自然发生的细胞凋亡。
