Costameric integrin and sarcoglycan protein levels are altered in a Drosophila model for Limb-girdle muscular dystrophy type 2H.
Costameric integrin and sarcoglycan protein levels are altered in a Drosophila model for Limb-girdle muscular dystrophy type 2H.
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DOI：
10.1091/mbc.e20-07-0453
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发表时间：
2021-02-01
影响因子：
3.3
通讯作者：
Geisbrecht ER
中科院分区：
文献类型：
--
作者：
Bawa S;Gameros S;Baumann K;Brooks DS;Kollhoff JA;Zolkiewski M;Re Cecconi AD;Panini N;Russo M;Piccirillo R;Johnson DK;Kashipathy MM;Battaile KP;Lovell S;Bouyain SEA;Kawakami J;Geisbrecht ER
普遍表达的TRIM32蛋白的两个不同结构域的突变导致两种临床不同的疾病，其中一种是2H型肢带肌营养不良症（LGMD2H）。揭示TRIM32在LGMD2H发病机制中的肌肉特异性作用已被证明是困难的，因为在TRIM32 KO小鼠中存在独立于LGMD2H病理的神经源性表型。我们之前以果蝇为模型建立了LGMD2H发病机制的研究平台。在这里，我们发现NHL结构域的LGMD2H致病突变在苍蝇和人类TRIM32之间在分子和结构上是保守的。此外，肌病等位基因亚群（R394H、D487N和520fs）的转基因表达可诱导肌原纤维异常、核形态改变和TRIM32蛋白水平降低，模拟LGMD2H患者的表型。有趣的是，我们还首次报道了βPS整合素和肌聚糖δ的蛋白水平在TRIM32致病等位基因中升高，这两种蛋白都是costameres的核心成分。同样，过度表达催化失活的TRIM32突变体的小鼠成肌细胞异常地积累α-和β-肌聚糖和α-肌聚糖。我们推测，化学计量损失的肋隔成分破坏肋隔复合物，促进肌肉变性。
Mutations in two different domains of the ubiquitously expressed TRIM32 protein give rise to two clinically separate diseases, one of which is Limb-girdle muscular dystrophy type 2H (LGMD2H). Uncovering the muscle-specific role of TRIM32 in LGMD2H pathogenesis has proven difficult, as neurogenic phenotypes, independent of LGMD2H pathology, are present in TRIM32 KO mice. We previously established a platform to study LGMD2H pathogenesis using Drosophila melanogaster as a model. Here we show that LGMD2H disease-causing mutations in the NHL domain are molecularly and structurally conserved between fly and human TRIM32. Furthermore, transgenic expression of a subset of myopathic alleles (R394H, D487N, and 520fs) induce myofibril abnormalities, altered nuclear morphology, and reduced TRIM32 protein levels, mimicking phenotypes in patients afflicted with LGMD2H. Intriguingly, we also report for the first time that the protein levels of βPS integrin and sarcoglycan δ, both core components of costameres, are elevated in TRIM32 disease-causing alleles. Similarly, murine myoblasts overexpressing a catalytically inactive TRIM32 mutant aberrantly accumulate α- and β-dystroglycan and α-sarcoglycan. We speculate that the stoichiometric loss of costamere components disrupts costamere complexes to promote muscle degeneration.