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首页> 外文期刊>Journal of Cachexia, Sarcopenia and Muscle >Functional phosphatome requirement for protein homeostasis, networked mitochondria, and sarcomere structure in C. elegans muscle
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Functional phosphatome requirement for protein homeostasis, networked mitochondria, and sarcomere structure in C. elegans muscle

机译：线虫肌肉中蛋白质稳态，网络线粒体和肌节结构的功能性磷原子需求

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Abstract Background Skeletal muscle is central to locomotion and metabolic homeostasis. The laboratory worm Caenorhabditis elegans has been developed into a genomic model for assessing the genes and signals that regulate muscle development and protein degradation. Past work has identified a receptor tyrosine kinase signalling network that combinatorially controls autophagy, nerve signal to muscle to oppose proteasome-based degradation, and extracellular matrix-based signals that control calpain and caspase activation. The last two discoveries were enabled by following up results from a functional genomic screen of known regulators of muscle. Recently, a screen of the kinome requirement for muscle homeostasis identified roughly 40% of kinases as required for C. elegans muscle health; 80 have identified human orthologues and 53 are known to be expressed in skeletal muscle. To complement this kinome screen, here, we screen most of the phosphatases in C. elegans . Methods RNA interference was used to knockdown phosphatase-encoding genes. Knockdown was first conducted during development with positive results also knocked down only in fully developed adult muscle. Protein homeostasis, mitochondrial structure, and sarcomere structure were assessed using transgenic reporter proteins. Genes identified as being required to prevent protein degradation were also knocked down in conditions that blocked proteasome or autophagic degradation. Genes identified as being required to prevent autophagic degradation were also assessed for autophagic vesicle accumulation using another transgenic reporter. Lastly, bioinformatics were used to look for overlap between kinases and phosphatases required for muscle homeostasis, and the prediction that one phosphatase was required to prevent mitogen-activated protein kinase activation was assessed by western blot. Results A little over half of all phosphatases are each required to prevent abnormal development or maintenance of muscle. Eighty-six of these phosphatases have known human orthologues, 57 of which are known to be expressed in human skeletal muscle. Of the phosphatases required to prevent abnormal muscle protein degradation, roughly half are required to prevent increased autophagy. Conclusions A significant portion of both the kinome and phosphatome are required for establishing and maintaining C. elegans muscle health. Autophagy appears to be the most commonly triggered form of protein degradation in response to disruption of phosphorylation-based signalling. The results from these screens provide measurable phenotypes for analysing the combined contribution of kinases and phosphatases in a multi-cellular organism and suggest new potential regulators of human skeletal muscle for further analysis.
机译：抽象背景骨骼肌是运动和代谢稳态的关键。实验室蠕虫秀丽隐杆线虫已经发展成为一种基因组模型，用于评估调节肌肉发育和蛋白质降解的基因和信号。过去的工作已经确定了一种受体酪氨酸激酶信号网络，该网络可组合地控制自噬，向肌肉发出的神经信号以对抗基于蛋白酶体的降解，以及基于细胞外基质的信号来控制钙蛋白酶和胱天蛋白酶的活化。通过跟踪已知肌肉调节剂的功能基因组筛查结果，可以实现最后两个发现。最近，通过筛查肌肉稳态所需的激酶，发现线虫肌肉健康所需的激酶约占40％。 80个已鉴定出人类直系同源物，而53个已知在骨骼肌中表达。为了补充这种激酶组筛选，在这里，我们筛选秀丽隐杆线虫中的大多数磷酸酶。方法使用RNA干扰来敲除磷酸酶编码基因。击倒是在发育过程中首先进行的，阳性结果也仅在成熟的成年肌肉中被击倒。使用转基因报告蛋白评估蛋白质稳态，线粒体结构和肌节结构。在阻止蛋白酶体或自噬降解的条件下，被鉴定为需要防止蛋白质降解的基因也被击倒。还使用另一种转基因报道基因评估了确定为需要预防自噬降解的基因的自噬囊泡积累。最后，生物信息学被用于寻找肌肉稳态所需的激酶和磷酸酶之间的重叠，并通过蛋白质印迹评估了一种磷酸酶需要阻止丝裂原活化的蛋白激酶活化的预测。结果所有磷酸酶的一半以上都需要防止肌肉异常发育或维持。这些磷酸酶中有八十六种已知人类直系同源物，其中57种已知在人类骨骼肌中表达。预防肌肉蛋白质异常降解所需的磷酸酶中，大约有一半需要预防自噬的增加。结论建立和维持秀丽隐杆线虫肌肉健康需要大量的激酶和磷原子。自噬似乎是响应基于磷酸化的信号转导的最普遍触发的蛋白质降解形式。这些筛选的结果提供了可测量的表型，用于分析多细胞生物体中激酶和磷酸酶的综合作用，并提出了人类骨骼肌潜在的新调节剂以供进一步分析。

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