The E3 ubiquitin ligase specificity subunit ASB2beta is a novel regulator of muscle differentiation that targets filamin B to proteasomal degradation.
The E3 ubiquitin ligase specificity subunit ASB2beta is a novel regulator of muscle differentiation that targets filamin B to proteasomal degradation.
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DOI：
10.1038/cdd.2009.27
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发表时间：
2009-06
影响因子：
12.4
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中科院分区：
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泛素介导的蛋白质降解是受控蛋白水解的主要机制，这对于肌肉的发育和维持至关重要。含有锚蛋白重复序列的蛋白质具有细胞因子信号传导盒 2 基因 (ASB2) 抑制因子，编码参与造血细胞分化的 E3 泛素连接酶复合物的特异性亚基。在这里，我们提供了第一个证据，证明一种新型 ASB2 亚型 ASB2β 对于肌肉分化很重要。 ASB2β 在胚胎发生期间和成体组织中的肌肉细胞中表达。 ASB2β 是活性 E3 泛素连接酶复合物的一部分，靶向肌动蛋白结合蛋白细丝蛋白 B (FLNb) 进行蛋白酶体降解。因此，ASB2β 通过控制 FLNb 的降解来调节 FLNb 的功能。在 C2C12 细胞诱导分化过程中，shRNA 敲低内源性 ASB2β 会延迟 FLNb 降解以及成肌细胞融合和肌肉收缩蛋白的表达。最后，在 ASB2β 敲低细胞中敲低 FLNb 可恢复肌原性分化。总而言之，我们的结果表明 ASB2β 通过靶向 FLNb 被蛋白酶体破坏而参与肌肉分化。
Ubiquitin-mediated protein degradation is the main mechanism for controlled proteolysis, which is crucial for muscle development and maintenance. The ankyrin repeat-containing protein with a suppressor of cytokine signalling box 2 gene (ASB2) encodes the specificity subunit of an E3 ubiquitin ligase complex involved in differentiation of hematopoietic cells. Here, we provide the first evidence that a novel ASB2 isoform, ASB2β, is important for muscle differentiation. ASB2β is expressed in muscle cells during embryogenesis and in adult tissues. ASB2β is part of an active E3 ubiquitin ligase complex and targets the actin-binding protein filamin B (FLNb) for proteasomal degradation. Thus, ASB2β regulates FLNb functions by controlling its degradation. Knockdown of endogenous ASB2β by shRNAs during induced-differentiation of C2C12 cells delayed FLNb degradation as well as myoblast fusion and expression of muscle contractile proteins. Finally, knockdown of FLNb in ASB2β knockdown cells restores myogenic differentiation. Altogether, our results suggest that ASB2β is involved in muscle differentiation through the targeting of FLNb to destruction by the proteasome.