Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA.
Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA.
Int J Mol Sci. 2021 Sep 1;22(17):9509. doi: 10.3390/ijms22179509.
As the largest tissue in the body, skeletal muscle has multiple functions in movement and energy metabolism. Skeletal myogenesis is controlled by a transcriptional cascade including a set of muscle regulatory factors (MRFs) that includes Myogenic Differentiation 1 (MYOD1), Myocyte Enhancer Factor 2 (MEF2), and Myogenin (MYOG), which direct the fusion of myogenic myoblasts into multinucleated myotubes. Neddylation is a posttranslational modification that covalently conjugates ubiquitin-like NEDD8 (neural precursor cell expressed, developmentally downregulated 8) to protein targets. Inhibition of neddylation impairs muscle differentiation; however, the underlying molecular mechanisms remain less explored. Here, we report that neddylation is temporally regulated during myoblast differentiation. Inhibition of neddylation through pharmacological blockade using MLN4924 (Pevonedistat) or genetic deletion of NEDD8 Activating Enzyme E1 Subunit 1 (NAE1), a subunit of the E1 neddylation-activating enzyme, blocks terminal myoblast differentiation partially through repressing MYOG expression. Mechanistically, we found that neddylation deficiency enhances the mRNA and protein expressions of class IIa histone deacetylases 4 and 5 (HDAC4 and 5) and prevents the downregulation and nuclear export of class III HDAC (NAD-Dependent Protein Deacetylase Sirtuin-1, SIRT1), all of which have been shown to repress MYOD1-mediated MYOG transcriptional activation. Together, our findings for the first time identify the crucial role of neddylation in mediating class IIa and III HDAC co-repressors to control myogenic program and provide new insights into the mechanisms of muscle disease and regeneration.
作为体内最大的组织，骨骼肌在运动和能量代谢中具有多种功能。骨骼肌发生是由一个转录级联控制的，其中包括一组肌肉调节因子（MRFs），包括肌源性分化 1（MYOD1）、肌细胞增强因子 2（MEF2）和肌生成素（MYOG），它们指导肌源性成肌细胞融合为多核肌管。Neddylation 是一种翻译后修饰，通过共价结合泛素样 NEDD8（神经前体细胞表达，发育下调 8）到蛋白靶标。Neddylation 的抑制会损害肌肉分化；然而，潜在的分子机制仍未得到充分探索。在这里，我们报告在成肌细胞分化过程中，Neddylation 是时间调节的。通过使用 MLN4924（Pevonedistat）或 NEDD8 激活酶 E1 亚基 1（NAE1）的遗传缺失来抑制 Neddylation（一种 E1 Neddylation-激活酶的亚基），可以部分阻断终末成肌细胞分化，部分通过抑制 MYOG 表达来阻断。从机制上讲，我们发现 Neddylation 缺乏会增强 IIa 类组蛋白去乙酰化酶 4 和 5（HDAC4 和 5）的 mRNA 和蛋白表达，并阻止 III 类 HDAC（NAD-依赖性蛋白去乙酰化酶 Sirtuin-1，SIRT1）的下调和核输出，所有这些都已被证明可以抑制 MYOD1 介导的 MYOG 转录激活。总之，我们的研究结果首次确定了 Neddylation 在介导 IIa 类和 III 类 HDAC 共抑制因子来控制肌生成程序中的关键作用，并为肌肉疾病和再生的机制提供了新的见解。
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