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首页> 外文期刊>Molecular and Cellular Biology >Chaperone Hsp27 Modulates AUF1 Proteolysis and AU-Rich Element-Mediated mRNA Degradation
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Chaperone Hsp27 Modulates AUF1 Proteolysis and AU-Rich Element-Mediated mRNA Degradation

机译：伴侣蛋白Hsp27调节AUF1蛋白水解和富AU元素介导的mRNA降解

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摘要

AUF1 is an AU-rich element (ARE)-binding protein that recruits translation initiation factors, molecular chaperones, and mRNA degradation enzymes to the ARE for mRNA destruction. We recently found chaperone Hsp27 to be an AUF1-associated ARE-binding protein required for tumor necrosis factor alpha (TNF-α) mRNA degradation in monocytes. Hsp27 is a multifunctional protein that participates in ubiquitination of proteins for their degradation by proteasomes. A variety of extracellular stimuli promote Hsp27 phosphorylation on three serine residues—Ser15, Ser78, and Ser82—by a number of kinases, including the mitogen-activated protein (MAP) pathway kinases p38 and MK2. Activating either kinase stabilizes ARE mRNAs. Likewise, ectopic expression of phosphomimetic mutant forms of Hsp27 stabilizes reporter ARE mRNAs. Here, we continued to examine the contributions of Hsp27 to mRNA degradation. As AUF1 is ubiquitinated and degraded by proteasomes, we addressed the hypothesis that Hsp27 phosphorylation controls AUF1 levels to modulate ARE mRNA degradation. Indeed, selected phosphomimetic mutants of Hsp27 promote proteolysis of AUF1 in a proteasome-dependent fashion and render ARE mRNAs more stable. Our results suggest that the p38 MAP kinase (MAPK)-MK2–Hsp27 signaling axis may target AUF1 destruction by proteasomes, thereby promoting ARE mRNA stabilization.
机译：AUF1是一种富含AU的元素（ARE）结合蛋白，可将翻译起始因子，分子伴侣和mRNA降解酶募集到ARE中以破坏mRNA。我们最近发现伴侣蛋白Hsp27是单核细胞中肿瘤坏死因子α（TNF-α）mRNA降解所需的AUF1相关的ARE结合蛋白。 Hsp27是一种多功能蛋白质，参与蛋白质的泛素化以通过蛋白酶体降解。多种细胞外刺激可通过多种激酶促进三个丝氨酸残基（Ser 15 ，Ser 78 和Ser 82 ）上的Hsp27磷酸化，包括促分裂原活化蛋白（MAP）途径激酶p38和MK2。激活任何一种激酶均可稳定ARE mRNA。同样，Hsp27的模拟磷酸化突变体形式的异位表达可稳定报告基因ARE mRNA。在这里，我们继续检查Hsp27对mRNA降解的贡献。由于AUF1被蛋白酶体泛素化和降解，我们提出了Hsp27磷酸化控制AUF1水平以调节ARE mRNA降解的假设。确实，Hsp27的选定的模拟磷酸化突变体以蛋白酶体依赖性的方式促进AUF1的蛋白水解，并使ARE mRNA更稳定。我们的结果表明，p38 MAP激酶（MAPK）-MK2-Hsp27信号轴可能靶向蛋白酶体破坏AUF1，从而促进ARE mRNA的稳定。

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