The cleavage of HuR interferes with its transportin-2-mediated nuclear import and promotes muscle fiber formation
The cleavage of HuR interferes with its transportin-2-mediated nuclear import and promotes muscle fiber formation
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DOI：
10.1038/cdd.2010.34
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发表时间：
2010-10-01
影响因子：
12.4
通讯作者：
Gallouzi, I-E
中科院分区：
文献类型：
--
作者：
Beauchamp, P.;Nassif, C.;Gallouzi, I-E
尽管转录后过程在调节参与肌纤维形成（肌生成）的基因表达中的功能已被广泛接受，但介导这些作用的机制仍然难以捉摸。在这里，我们揭示了这样的机制，并表明，在肌生成过程中，转录后调节因子人抗原R（HuR）的一部分被切割在细胞培养和动物模型中的半胱天冬酶依赖的方式。在培养的成肌细胞中破坏半胱天冬酶活性或敲除小鼠中的半胱天冬酶-3基因显著降低了HuR切割和肌纤维中HuR的细胞质积累。HuR的不可切割的同种型HuRD 226 A未能重建HuR耗尽的成肌细胞的肌生成潜能。HuR裂解产生两个片段：HuR裂解产物1（HuR-CP 1）（24 kDa）和HuR-CP 2（8 kDa）。在这里，我们表明，这些片段之一（HuR-CP 1）结合到HuR输入因子转运蛋白2（TRN 2），使HuR积累在细胞质中。由于HuR的促肌原功能需要这种细胞质积累，因此我们的数据支持一种模型，即在从成肌细胞到肌管的过渡阶段，一定比例的HuR被切割以产生HuR-CP 1。通过干扰TRN 2介导的HuR输入，该CP帮助未切割的HuR在细胞质中积累，从而促进肌生成。Cell Death and Differentiation（2010）17，1588-1599; doi：10.1038/cdd.2010.34; 2010年4月9日在线发表
Although the function of posttranscriptional processes in regulating the expression of genes involved in muscle fiber formation (myogenesis) is well accepted, the mechanisms by which these effects are mediated remain elusive. Here, we uncover such a mechanism and show that during myogenesis, a fraction of the posttranscriptional regulator human antigen R (HuR) is cleaved in a caspase-dependent manner in both cell culture and animal models. Disruption of caspase activity in cultured myoblasts or knocking out the caspase-3 gene in mice significantly reduced HuR cleavage and the cytoplasmic accumulation of HuR in muscle fibers. The non-cleavable isoform of HuR, HuRD226A, failed to reestablish the myogenic potential of HuR-depleted myoblasts. HuR cleavage generates two fragments: HuR-cleavage product 1 (HuR-CP1) (24 kDa) and HuR-CP2 (8 kDa). Here, we show that one of these fragments (HuR-CP1) binds to the HuR import factor transportin-2 (TRN2) allowing HuR to accumulate in the cytoplasm. As this cytoplasmic accumulation is required for the promyogenic function of HuR, our data support a model, whereby during the transition phase from myoblasts to myotubes, a proportion of HuR is cleaved to generate HuR-CP1. By interfering with the TRN2-mediated import of HuR, this CP helps non-cleaved HuR accumulate in the cytoplasm thus promoting myogenesis. Cell Death and Differentiation (2010) 17, 1588-1599; doi:10.1038/cdd.2010.34; published online 9 April 2010