Regnase-1 and Roquin Regulate a Common Element in Inflammatory mRNAs by Spatiotemporally Distinct Mechanisms
Regnase-1 and Roquin Regulate a Common Element in Inflammatory mRNAs by Spatiotemporally Distinct Mechanisms
复制标题
DOI：
10.1016/j.cell.2015.04.029
复制
发表时间：
2015-05-21
期刊：
影响因子：
64.5
通讯作者：
Takeuchi, Osamu
中科院分区：
文献类型：
--
作者：
Mino, Takashi;Murakawa, Yasuhiro;Takeuchi, Osamu
regase -1和Roquin是降解炎症相关mrna和维持免疫稳态所必需的RNA结合蛋白。然而，它们之间的机制关系尚不清楚。在这里，我们表明，尽管Regnase-1和Roquin通过一个共同的茎环结构调节一组重叠的mrna，但它们分别在不同的亚细胞位置起作用：核糖体/内质网和加工体/应激颗粒。此外，regase -1特异性地切割和降解翻译活性mrna，并需要UPF1的解旋酶活性，类似于无义mrna的衰变机制。相比之下，Roquin控制翻译非活性mrna，独立于UPF1。Regnase-1和Roquin的缺陷导致其靶mrna的大量增加，尽管Regnase-1倾向于控制炎症的早期阶段，此时mrna被更积极地翻译。我们的研究结果表明，Regnase-1和Roquin对mrna的差异调节取决于它们的翻译状态，并能够精细地控制炎症。
Regnase-1 and Roquin are RNA binding proteins essential for degradation of inflammation-related mRNAs and maintenance of immune homeostasis. However, their mechanistic relationship has yet to be clarified. Here, we show that, although Regnase-1 and Roquin regulate an overlapping set of mRNAs via a common stem-loop structure, they function in distinct subcellular locations: ribosome/endoplasmic reticulum and processing-body/stress granules, respectively. Moreover, Regnase-1 specifically cleaves and degrades translationally active mRNAs and requires the helicase activity of UPF1, similar to the decay mechanisms of nonsense mRNAs. In contrast, Roquin controls translationally inactive mRNAs, independent of UPF1. Defects in both Regnase-1 and Roquin lead to large increases in their target mRNAs, although Regnase-1 tends to control the early phase of inflammation when mRNAs are more actively translated. Our findings reveal that differential regulation of mRNAs by Regnase-1 and Roquin depends on their translation status and enables elaborate control of inflammation.