Dystroglycan is not required for localization of dystrophin, syntrophin, and neuronal nitric-oxide synthase at the sarcolemma but regulates integrin α7B expression and caveolin-3 distribution
Dystroglycan is not required for localization of dystrophin, syntrophin, and neuronal nitric-oxide synthase at the sarcolemma but regulates integrin α7B expression and caveolin-3 distribution
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DOI：
10.1074/jbc.m106879200
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发表时间：
2002-02-15
影响因子：
4.8
通讯作者：
Carbonetto, S
中科院分区：
文献类型：
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作者：
Côté, PD;Moukhles, H;Carbonetto, S
肌营养不良聚糖是肌营养不良蛋白相关蛋白复合物的一部分，它将细胞外基质中的层粘连蛋白与肌膜下细胞骨架内的肌营养不良蛋白连接起来。我们通过使用免疫组织化学和免疫印迹比较小鼠的 merosin（α（2）-层粘连蛋白，dy）、肌营养不良蛋白（mdx）和肌营养不良蛋白（Dag1）突变体，研究了层粘连蛋白-肌营养不良聚糖-肌营养不良蛋白轴成分的突变如何影响肌营养不良蛋白相关蛋白的组织和表达。我们报告说，在缺乏肌营养不良蛋白和肌营养不良聚糖的肌纤维中，肌营养不良蛋白和神经元一氧化氮合酶被耗尽。然而，一些缺乏肌营养不良聚糖的纤维将肌营养不良蛋白定位在细胞表面，其水平与野生型肌肉中的水平相似。然而，这些纤维具有变性/再生的迹象，包括细胞表面渗透性和中央细胞核增加。在这些纤维中，肌营养蛋白和一氧化氮合酶也定位于质膜，而肌聚糖复合物则被破坏。这些结果表明肌营养不良蛋白的膜附着机制不依赖于肌营养不良聚糖，并且肌聚糖与肌营养不良蛋白的相互作用需要肌营养不良聚糖。 Caveolin-3（最近发现与肌营养不良聚糖结合的小窝的肌肉特异性成分）的分布在肌营养不良聚糖和肌营养不良蛋白缺陷的小鼠中受到影响。我们还检查了细胞-细胞外基质附着的替代机制，以阐明肌肉基底膜如何在缺乏肌营养不良聚糖的情况下生存，并且我们发现 α(7) 整联蛋白受体亚基的 α(7B) 剪接变体上调。这些结果支持α(7B)整合素补偿介导细胞-细胞外基质附着但不能挽救营养不良表型的可能性。
Dystroglycan is part of the dystrophin-associated protein complex, which joins laminin in the extracellular matrix to dystrophin within the subsarcolemmal cytoskeleton. We have investigated how mutations in the components of the laminin-dystroglycan-dystrophin axis affect the organization and expression of dystrophin-associated proteins by comparing mice mutant for merosin (alpha(2)-laminin, dy), dystrophin (mdx), and dystroglycan (Dag1) using immunohistochemistry and immunoblots. We report that syntrophin and neuronal nitric-oxide synthase are depleted in muscle fibers lacking both dystrophin and dystroglycan. Some fibers deficient in dystroglycan, however, localize dystrophin at the cell surface at levels similar to that in wild-type muscle. Nevertheless, these fibers have signs of degeneration/regeneration including increased cell surface permeability and central nuclei. In these fibers, syntrophin and nitric-oxide synthase are also localized to the plasma membrane, whereas the sarcoglycan complex is disrupted. These results suggest a mechanism of membrane attachment for dystrophin independent of dystroglycan and that the interaction of sarcoglycans with dystrophin requires dystroglycan. The distribution of caveolin-3, a muscle-specific component of caveolae recently found to bind dystroglycan, was affected in dystroglycan- and dystrophin-deficient mice. We also examined alternative mechanisms of cell-extracellular matrix attachment to elucidate how the muscle basement membrane may subsist in the absence of dystroglycan, and we found the alpha(7B) splice variant of the alpha(7) integrin receptor subunit to be up-regulated. These results support the possibility that alpha(7B) integrin compensates in mediating cell-extracellular matrix attachment but cannot rescue the dystrophic phenotype.