The ER-bound RING finger protein 5 (RNF5/RMA1) causes degenerative myopathy in transgenic mice and is deregulated in inclusion body myositis.
The ER-bound RING finger protein 5 (RNF5/RMA1) causes degenerative myopathy in transgenic mice and is deregulated in inclusion body myositis.
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ER结合的环手指蛋白5（RNF5/RMA1）在转基因小鼠中引起退化性肌病，并在包容体肌炎中受管制。
DOI：
10.1371/journal.pone.0001609
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发表时间：
2008-02-13
期刊：
影响因子：
3.7
通讯作者：
Ronai, Ze'ev
中科院分区：
文献类型：
--
作者：
Delaunay, Agnes;Bromberg, Kenneth D.;Hayashi, Yukiko;Mirabella, Massimiliano;Burch, Denise;Kirkwood, Brian;Serra, Carlo;Malicdan, May C.;Mizisin, Andrew P.;Morosetti, Roberta;Broccolini, Aldobrando;Guo, Ling T.;Jones, Stephen N.;Lira, Sergio A.;Puri, Pier Lorenzo;Shelton, G. Diane;Ronai, Ze'ev
越来越多的证据支持泛素连接酶在肌肉疾病发病机制中的重要性，尽管其潜在机制在很大程度上仍然难以捉摸。在这里，我们表明，表达RNF 5（又名RMA 1），ER锚定的环指E3连接酶参与肌肉组织和识别和处理错误折叠的蛋白质，是升高和错误定位到细胞质聚集体活检患者患有散发性包涵体肌炎（sIBM）。与这些发现一致，遗传性IBM（hIBM）的动物模型，但不是他们的对照同窝仔，揭示了RNF 5的表达失调。使用RNF 5转基因和KO动物对RNF 5在s-IBM发病机制中的作用以及更一般地在肌肉生理学中的作用进行了进一步的研究。在β-肌动蛋白或肌肉特异性启动子的控制下，携带可诱导表达的RNF 5的转基因小鼠表现出肌肉萎缩、肌肉变性和广泛的纤维再生的早期发作。RNF 5在肌肉中的延长表达也导致含有嗜酸性物质的纤维、蓝边空泡和包涵体的形成。这些表型与ER分子伴侣的表达和活性改变相关，这是肌变性疾病如s-IBM的特征。相反，肌肉再生和ER应激标志物的诱导延迟RNF 5基因敲除小鼠心脏毒素治疗。在支持RNF 5 Tg小鼠作为s-IBM模型的作用的同时，我们的研究还确定了RNF 5在肌肉生理学中的重要性及其在ER应激相关肌肉疾病中的失调。
Growing evidence supports the importance of ubiquitin ligases in the pathogenesis of muscular disorders, although underlying mechanisms remain largely elusive. Here we show that the expression of RNF5 (aka RMA1), an ER-anchored RING finger E3 ligase implicated in muscle organization and in recognition and processing of malfolded proteins, is elevated and mislocalized to cytoplasmic aggregates in biopsies from patients suffering from sporadic-Inclusion Body Myositis (sIBM). Consistent with these findings, an animal model for hereditary IBM (hIBM), but not their control littermates, revealed deregulated expression of RNF5. Further studies for the role of RNF5 in the pathogenesis of s-IBM and more generally in muscle physiology were performed using RNF5 transgenic and KO animals. Transgenic mice carrying inducible expression of RNF5, under control of β-actin or muscle specific promoter, exhibit an early onset of muscle wasting, muscle degeneration and extensive fiber regeneration. Prolonged expression of RNF5 in the muscle also results in the formation of fibers containing congophilic material, blue-rimmed vacuoles and inclusion bodies. These phenotypes were associated with altered expression and activity of ER chaperones, characteristic of myodegenerative diseases such as s-IBM. Conversely, muscle regeneration and induction of ER stress markers were delayed in RNF5 KO mice subjected to cardiotoxin treatment. While supporting a role for RNF5 Tg mice as model for s-IBM, our study also establishes the importance of RNF5 in muscle physiology and its deregulation in ER stress associated muscular disorders.
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影响因子：
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作者：
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MIRA, JC