State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
EMBO J. 2019 Sep 2;38(17):e101051. doi: 10.15252/embj.2018101051. Epub 2019 Jul 22.
VGLL4 has previously been identified as a negative regulator of YAP. Here we show that VGLL4 regulates muscle regeneration in both YAP-dependent and YAP-independent manners at different stages. Knockout of VGLL4 in mice leads to smaller myofiber size and defective muscle contraction force. Furthermore, our studies reveal that knockout of VGLL4 results in increased muscle satellite cells proliferation and impaired myoblast differentiation, which ultimately leads to delayed muscle regeneration. Mechanistically, the results show that VGLL4 works as a conventional repressor of YAP at the proliferation stage of muscle regeneration. At the differentiation stage, VGLL4 acts as a co-activator of TEAD4 to promote MyoG transactivation and facilitate the initiation of differentiation in a YAP-independent manner. Moreover, VGLL4 stabilizes the protein-protein interactions between MyoD and TEAD4 to achieve efficient MyoG transactivation. Our findings define the dual roles of VGLL4 in regulating muscle regeneration at different stages and may open novel therapeutic perspectives for muscle regeneration.
VGLL4 先前被鉴定为 YAP 的负调控因子。在这里，我们展示了 VGLL4 在不同阶段以 YAP 依赖和非依赖的方式调节肌肉再生。VGLL4 在小鼠中的敲除导致肌纤维大小减小和肌肉收缩力缺陷。此外，我们的研究表明，VGLL4 的敲除导致肌肉卫星细胞增殖增加和成肌细胞分化受损，最终导致肌肉再生延迟。从机制上讲，结果表明 VGLL4 在肌肉再生的增殖阶段作为 YAP 的传统抑制剂发挥作用。在分化阶段，VGLL4 作为 TEAD4 的共激活因子发挥作用，促进 MyoG 的转录激活，并以 YAP 非依赖的方式促进分化的启动。此外，VGLL4 稳定了 MyoD 和 TEAD4 之间的蛋白质-蛋白质相互作用，以实现有效的 MyoG 转录激活。我们的发现定义了 VGLL4 在不同阶段调节肌肉再生的双重作用，并可能为肌肉再生开辟新的治疗视角。
