IRE1-XBP1 Pathway of the Unfolded Protein Response Is Required during Early Differentiation of C2C12 Myoblasts
IRE1-XBP1 Pathway of the Unfolded Protein Response Is Required during Early Differentiation of C2C12 Myoblasts
复制标题
DOI：
10.3390/ijms21010182
复制
发表时间：
2020-01-01
影响因子：
5.6
通讯作者：
Yonekura, Shinichi
中科院分区：
文献类型：
--
作者：
Tokutake, Yukako;Yamada, Keita;Yonekura, Shinichi
在骨骼肌中，成肌细胞分化导致多核肌纤维的形成。尽管最近的研究表明未折叠蛋白反应（UPR）在细胞内重塑中发挥重要作用并有助于骨骼肌分化，但主要 UPR 信号通路 IRE1-XBP1 信号通路的参与仍不清楚。本研究旨在探讨IRE1-XBP1通路对骨骼肌分化的影响。在 C2C12 细胞中，细胞中 IRE1 和 XBP1 的敲除显着抑制了分化。此外，XBP1 敲低细胞中的细胞凋亡和自噬显着增强，突出显示 IRE1-XBP1 在骨骼肌分化过程中通过分化刺激参与细胞存活维持。在肌原性细胞中，我们证明CDK5（细胞周期蛋白依赖性激酶5）的表达受到XBP1的调节，并且我们提出XBP1通过诱导CDK5来调节MyoD家族基因的表达。总之，这项研究表明，IRE1-XBP1 信号在预分化成肌细胞和早期分化阶段的细胞活力和分化相关基因的表达中发挥着关键作用。
In skeletal muscle, myoblast differentiation results in the formation of multinucleated myofibers. Although recent studies have shown that unfolded protein responses (UPRs) play an important role in intracellular remodeling and contribute to skeletal muscle differentiation, the involvement of IRE1-XBP1 signaling, a major UPR signaling pathway, remains unclear. This study aimed to investigate the effect of the IRE1-XBP1 pathway on skeletal muscle differentiation. In C2C12 cells, knockdown of IRE1 and XBP1 in cells remarkably suppressed differentiation. In addition, apoptosis and autophagy were dramatically enhanced in the XBP1-knockdown cells, highlighting the participation of IRE1-XBP1 in cell survival maintenance with differentiation stimuli during skeletal muscle differentiation. In myogenic cells, we demonstrated that the expression of CDK5 (cyclin-dependent kinase 5) is regulated by XBP1s, and we propose that XBP1 regulates the expression of MyoD family genes via the induction of CDK5. In conclusion, this study revealed that IRE1-XBP1 signaling plays critical roles in cell viability and the expression of differentiation-related genes in predifferentiated myoblasts and during the early differentiation phase.