Nastasi Tommaso, Bongiovanni Antonella, Campos Yvan, Mann Linda, Toy James N, Bostrom Jake, Rottier Robbert, Hahn Christopher, Conaway Joan Weliky, Harris A John, D'Azzo Alessandra
Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105, USA.
Dev Cell. 2004 Feb;6(2):269-82. doi: 10.1016/s1534-5807(04)00020-6.
The identities of the ubiquitin-ligases active during myogenesis are largely unknown. Here we describe a RING-type E3 ligase complex specified by the adaptor protein, Ozz, a novel SOCS protein that is developmentally regulated and expressed exclusively in striated muscle. In mice, the absence of Ozz results in overt maturation defects of the sarcomeric apparatus. We identified beta-catenin as one of the target substrates of the Ozz-E3 in vivo. In the differentiating myofibers, Ozz-E3 regulates the levels of sarcolemma-associated beta-catenin by mediating its degradation via the proteasome. Expression of beta-catenin mutants that reduce the binding of Ozz to endogenous beta-catenin leads to Mb-beta-catenin accumulation and myofibrillogenesis defects similar to those observed in Ozz null myocytes. These findings reveal a novel mechanism of regulation of Mb-beta-catenin and the role of this pool of the protein in myofibrillogenesis, and implicate the Ozz-E3 ligase in the process of myofiber differentiation.
在肌生成过程中发挥作用的泛素连接酶的身份在很大程度上尚不清楚。在此，我们描述了一种由衔接蛋白Ozz指定的RING型E3连接酶复合物，Ozz是一种新型的SOCS蛋白，其表达受发育调控且仅在横纹肌中表达。在小鼠中，Ozz的缺失导致肌节装置出现明显的成熟缺陷。我们在体内确定β-连环蛋白是Ozz-E3的靶底物之一。在分化的肌纤维中，Ozz-E3通过介导β-连环蛋白经蛋白酶体降解来调节肌膜相关β-连环蛋白的水平。降低Ozz与内源性β-连环蛋白结合的β-连环蛋白突变体的表达会导致Mb-β-连环蛋白积累以及肌原纤维生成缺陷，这与在Ozz基因敲除的心肌细胞中观察到的情况相似。这些发现揭示了调节Mb-β-连环蛋白的新机制以及该蛋白池在肌原纤维生成中的作用，并表明Ozz-E3连接酶参与了肌纤维分化过程。
