Cullin E3 Ligase Activity Is Required for Myoblast Differentiation.
Cullin E3 Ligase Activity Is Required for Myoblast Differentiation.
复制标题
DOI：
10.1016/j.jmb.2017.02.012
复制
发表时间：
2017-04-07
影响因子：
5.6
通讯作者：
Lange S
中科院分区：
文献类型：
--
作者：
Blondelle J;Shapiro P;Domenighetti AA;Lange S
在肌肉萎缩过程中，cullin E3-泛素连接酶在肌肉内稳中的作用最为人所知，因为cullin-1底物接头阿托金-1是最具特征的肌肉萎缩蛋白之一。我们研究了在成肌细胞终末分化和乙酰胆碱受体聚集过程中，cullin活性是否也是建立体外神经肌肉连接的关键。Cullin E3-连接酶的活性通过小泛素样修饰物NEDD8的翻译后修饰来调节。用Nae1抑制剂MLN4924(PevoneDistat)或针对分化早期或晚期NEDD8的siRNA对C2C12成肌细胞以及来自鼠和人的原代卫星细胞进行的研究表明，cullin E3-连接酶活性在体外肌肉细胞分化程序的每一步都是必需的。我们进一步研究了已知的肌肉末端分化的转录抑制因子ZBTB38、BHLHE41和Id1。由于它们在肌肉终末分化中的作用，我们推测这些潜在的cullin E3-连接酶底物的积累可能是观察到的表型的部分原因。MLN4924目前正在癌症患者身上进行临床试验，我们的实验突出了对这些经常经历恶病质的患者肌肉的动态平衡和再生能力的担忧。
The role of cullin E3-ubiquitin ligases for muscle homeostasis is best known during muscle atrophy, as the cullin-1 substrate adaptor atrogin-1 counts among the most well-characterized muscle atrogins. We investigated, whether cullin activity was also crucial during terminal myoblast differentiation and aggregation of acetylcholine receptors for the establishment of neuromuscular junctions in vitro. The activity of cullin E3-ligases is modulated through posttranslational modification with the small ubiquitin-like modifier nedd8. Using either the Nae1 inhibitor MLN4924 (Pevonedistat) or siRNA against nedd8 in early or late stages of differentiation on C2C12 myoblasts, and primary satellite cells from mouse and human, we show that cullin E3-ligase activity is necessary for each step of the muscle cell differentiation program in vitro. We further investigate known transcriptional repressors for terminal muscle differentiation ZBTB38, Bhlhe41 and Id1. Due to their identified roles for terminal muscle differentiation, we hypothesize that accumulation of these potential cullin E3-ligase substrates may be partially responsible for the observed phenotype. MLN4924 is currently undergoing clinical trials in cancer patients, and our experiments highlight concerns on the homeostasis and regenerative capacity of muscles in these patients who often experience cachexia.
细胞骨架在培养的肌肉细胞中乙酰胆碱受体簇的形成，稳定和去除中的作用。
影响因子：
7.8
作者：
Connolly, J A
通讯作者：
Connolly, J A