TNF-α increases ubiquitin-conjugating activity in skeletal muscle by up-regulating UbcH2/E220k
TNF-α increases ubiquitin-conjugating activity in skeletal muscle by up-regulating UbcH2/E220k
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DOI：
10.1096/fj.02-0759com
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发表时间：
2003-06-01
期刊：
影响因子：
4.8
通讯作者：
Reid, MB
中科院分区：
文献类型：
--
作者：
Li, YP;Lecker, SH;Reid, MB
在一些炎性疾病中，TNF-α被认为通过增加泛素与肌肉蛋白结合的NF-κ B依赖性过程刺激肌肉catalysis。这种反应的转录机制尚未确定。在这里，我们研究了UbcH 2的潜在作用，UbcH 2是一种泛素载体蛋白，也是小鼠E2（20 k）的同源物。我们发现，UbcH 2是组成型表达的人骨骼肌和心肌，小鼠肢体肌肉，和培养的肌管。TNF-α在体内和培养的肌管中刺激小鼠肢体肌肉中UbcH 2的表达。UbcH 2启动子区含有功能性NF-κ B结合位点; TNF-α刺激可增加NF-κ B与该序列的结合。一种显性负性NF-κ B激活抑制剂阻断了UbcH 2的上调和TNF-α刺激的泛素结合活性的增加。在TNF-α处理的肌管提取物中，泛素结合活性受到UbcH 2可用性的限制;活性被UbcH 2的抗血清或UbcH 2的显性负突变体抑制，并被野生型UbcH 2增强。因此，UbcH 2上调是骨骼肌中对TNF-α/NF-κ B信号传导的一种新的应答，其对于由该细胞因子诱导的增加的泛素缀合似乎是必需的。
In some inflammatory diseases, TNF-alpha is thought to stimulate muscle catabolism via an NF-kappaB-dependent process that increases ubiquitin conjugation to muscle proteins. The transcriptional mechanism of this response has not been determined. Here we studied the potential role of UbcH2, a ubiquitin carrier protein and homologue of murine E2(20k). We find that UbcH2 is constitutively expressed by human skeletal and cardiac muscles, murine limb muscle, and cultured myotubes. TNF-alpha stimulates UbcH2 expression in mouse limb muscles in vivo and in cultured myotubes. The UbcH2 promoter region contains a functional NF-kappaB binding site; NF-kappaB binding to this sequence is increased by TNF-alpha stimulation. A dominant negative inhibitor of NF-kappaB activation blocks both UbcH2 up-regulation and the increase in ubiquitin-conjugating activity stimulated by TNF-alpha. In extracts from TNF-alpha-treated myotubes, ubiquitin-conjugating activity is limited by UbcH2 availability; activity is inhibited by an antiserum to UbcH2 or a dominant negative mutant of UbcH2 and is enhanced by wild-type UbcH2. Thus, UbcH2 upregulation is a novel response to TNF-alpha/NF-kappaB signaling in skeletal muscle that appears to be essential for the increased ubiquitin conjugation induced by this cytokine.