The myosin-interacting protein SMYD1 is essential for sarcomere organization
The myosin-interacting protein SMYD1 is essential for sarcomere organization
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DOI：
10.1242/jcs.084772
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发表时间：
2011-09-15
影响因子：
4
通讯作者：
Rottbauer, Wolfgang
中科院分区：
文献类型：
--
作者：
Just, Steffen;Meder, Benjamin;Rottbauer, Wolfgang
肌节的组装、维持和更新需要肌节蛋白的高度组织化和平衡的折叠、运输、修饰和降解。然而，介导这些过程的分子在很大程度上是未知的。在这里，我们分离的斑马鱼突变体flatline（弗拉），这表明干扰肌节组装专门在心脏和快速收缩骨骼肌。通过定位克隆，我们确定了一个无义突变的SET和MYND结构域的蛋白1基因（small 1）负责的弗拉表型。我们发现SMYD 1的表达仅限于心脏和快速收缩骨骼肌细胞。在这些细胞类型中，SMYD 1定位于肌节M线和细胞核，在那里它与肌球蛋白物理结合，在那里它通过SET和MYND结构域抑制转录。然而，尽管我们发现厚丝分子伴侣（如Hsp 90 a1和Hsp 45 b）的转录水平在弗拉中严重上调，但其组蛋白甲基转移酶活性-主要负责SMYD 1的核功能-与肌角化有关。因此，弗拉突变胚胎中的肌节组装可以通过异位表达组蛋白甲基转移酶缺陷型SMYD 1来重建。相比之下，肌球蛋白结合缺陷型SMYD 1的异位表达不能挽救弗拉突变体，这暗示了SMYD 1-肌球蛋白相互作用在心脏和快收缩骨骼肌粗丝组装中的重要作用。
Assembly, maintenance and renewal of sarcomeres require highly organized and balanced folding, transport, modification and degradation of sarcomeric proteins. However, the molecules that mediate these processes are largely unknown. Here, we isolated the zebrafish mutant flatline (fla), which shows disturbed sarcomere assembly exclusively in heart and fast-twitch skeletal muscle. By positional cloning we identified a nonsense mutation within the SET-and MYND-domain-containing protein 1 gene (smyd1) to be responsible for the fla phenotype. We found SMYD1 expression to be restricted to the heart and fast-twitch skeletal muscle cells. Within these cell types, SMYD1 localizes to both the sarcomeric M-line, where it physically associates with myosin, and the nucleus, where it supposedly represses transcription through its SET and MYND domains. However, although we found transcript levels of thick filament chaperones, such as Hsp90a1 and UNC-45b, to be severely upregulated in fla, its histone methyltransferase activity - mainly responsible for the nuclear function of SMYD1 - is dispensable for sarcomerogenesis. Accordingly, sarcomere assembly in fla mutant embryos can be reconstituted by ectopically expressing histone methyltransferase-deficient SMYD1. By contrast, ectopic expression of myosin-binding-deficient SMYD1 does not rescue fla mutants, implicating an essential role for the SMYD1-myosin interaction in cardiac and fast-twitch skeletal muscle thick filament assembly.