Chaperone Hsp27, a Novel Subunit of AUF1 Protein Complexes, Functions in AU-Rich Element-Mediated mRNA Decay
Chaperone Hsp27, a Novel Subunit of AUF1 Protein Complexes, Functions in AU-Rich Element-Mediated mRNA Decay
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DOI：
10.1128/mcb.00431-08
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发表时间：
2008-06
影响因子：
5.3
通讯作者：
Kristina S. Sinsimer;Frances M. Gratacós;A. Knapinska;Jiebo Lu;Christopher D. Krause;Alexandria V Wierzbowski;Lauren R. Maher;S. Scrudato;Y. Rivera;Swati Gupta;Danielle K. Turrin;Mary Pauline De La Cruz;S. Pestka;G. Brewer
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文献类型：
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作者：
Kristina S. Sinsimer;Frances M. Gratacós;A. Knapinska;Jiebo Lu;Christopher D. Krause;Alexandria V Wierzbowski;Lauren R. Maher;S. Scrudato;Y. Rivera;Swati Gupta;Danielle K. Turrin;Mary Pauline De La Cruz;S. Pestka;G. Brewer
单核细胞的细胞因子的产生主要依赖于mRNA的快速降解，这是由与RNA结合蛋白相关的3′端非翻译区富含AU的元件（战神）实现的。ARE结合蛋白AUF 1与帽依赖性翻译起始因子和热休克蛋白形成复合物以吸引mRNA降解机制。我们将这种蛋白质组装体称为AUF 1和信号转导调节复合物（ASTRC）。携带ARE的mRNA（ARE-mRNAs）的快速降解需要AUF 1的泛素化及其被蛋白酶体破坏。单核细胞通过粘附到组织损伤部位的毛细血管内皮而活化以及随后的促炎细胞因子诱导是炎症的突出特征，并且ARE-mRNA稳定化在诱导过程中起关键作用。在这里，我们证明了激活诱导的ASTRC内的亚基重排，并确定伴侣Hsp 27作为一种新的亚基，本身是一个ARE结合蛋白快速ARE-mRNA降解必不可少的。由于Hsp 27在蛋白质泛素化以及粘附诱导的细胞骨架重塑和细胞运动中具有良好的特征化作用，其与ASTRC的关联可能提供了将促炎细胞因子诱导与单核细胞粘附和运动耦合的传感机制。
ABSTRACT Controlled, transient cytokine production by monocytes depends heavily upon rapid mRNA degradation, conferred by 3′ untranslated region-localized AU-rich elements (AREs) that associate with RNA-binding proteins. The ARE-binding protein AUF1 forms a complex with cap-dependent translation initiation factors and heat shock proteins to attract the mRNA degradation machinery. We refer to this protein assembly as the AUF1- and signal transduction-regulated complex, ASTRC. Rapid degradation of ARE-bearing mRNAs (ARE-mRNAs) requires ubiquitination of AUF1 and its destruction by proteasomes. Activation of monocytes by adhesion to capillary endothelium at sites of tissue damage and subsequent proinflammatory cytokine induction are prominent features of inflammation, and ARE-mRNA stabilization plays a critical role in the induction process. Here, we demonstrate activation-induced subunit rearrangements within ASTRC and identify chaperone Hsp27 as a novel subunit that is itself an ARE-binding protein essential for rapid ARE-mRNA degradation. As Hsp27 has well-characterized roles in protein ubiquitination as well as in adhesion-induced cytoskeletal remodeling and cell motility, its association with ASTRC may provide a sensing mechanism to couple proinflammatory cytokine induction with monocyte adhesion and motility.