Dual function of VGLL4 in muscle regeneration
Dual function of VGLL4 in muscle regeneration
复制标题
VGLL4 在肌肉再生中的双重功能
DOI：
10.15252/embj.2018101051
复制
发表时间：
2019-07-22
期刊：
影响因子：
11.4
通讯作者：
Zhang, Lei
中科院分区：
文献类型：
--
作者：
Feng, Xue;Wang, Zuoyun;Zhang, Lei
VGLL4 先前已被确定为 YAP 的负调节因子。在这里，我们表明 VGLL4 在不同阶段以 YAP 依赖和 YAP 独立的方式调节肌肉再生。小鼠中 VGLL4 的敲除会导致肌纤维尺寸变小和肌肉收缩力缺陷。此外，我们的研究表明，敲除 VGLL4 会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充当 YAP 的常规抑制剂。在分化阶段，VGLL4 作为 TEAD4 的共激活剂，促进 MyoG 反式激活，并以不依赖 YAP 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 反式激活。我们的研究结果定义了 VGLL4 在不同阶段调节肌肉再生中的双重作用，并可能为肌肉再生开辟新的治疗前景。
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.