HuR counteracts miR-330 to promote STAT3 translation during inflammation-induced muscle wasting
HuR counteracts miR-330 to promote STAT3 translation during inflammation-induced muscle wasting
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DOI：
10.1073/pnas.1905172116
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发表时间：
2019-08-27
影响因子：
11.1
通讯作者：
Gallouzi, Imed-Eddine
中科院分区：
文献类型：
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作者：
Mubaid, Souad;Ma, Jennifer F.;Gallouzi, Imed-Eddine
癌症引起的肌肉萎缩（一种称为恶病质的综合症）是致命的。在此，我们报告了一条涉及 RNA 结合蛋白 HuR 的转录后通路，该通路在该综合征的发病过程中发挥着关键作用。在这些条件下，HuR 将其功能从肌纤维形成的促进剂转变为肌肉损失的诱导剂。 HuR 与 STAT3（信号转导子和转录激活子 3）mRNA 结合，该 mRNA 编码这种情况的主要效应子之一，从而促进其在体外和体内的表达。虽然 HuR 不会影响该转录物的稳定性和细胞运动，但 HuR 通过阻止 miR-330 (microRNA 330) 介导的翻译抑制来促进 STAT3 mRNA 的翻译。为了实现这一效果，HuR 直接与位于 miR-330 种子元件附近的 STAT3 mRNA-3' 非翻译区 (UTR) 中富含 U 的元件结合。尽管 HuR 和 miR-330 的结合位点不重叠，但将其中任何一个因子招募到 STAT3-3' UTR 都会对另一个因子的结合和功能产生负面影响。因此，我们的数据共同确定了 HuR 和 miR-330 之间的竞争性相互作用，作为一种机制，肌纤维通过该机制部分调节 STAT3 表达，以确定它们响应肌肉萎缩启动子的命运。
Debilitating cancer-induced muscle wasting, a syndrome known as cachexia, is lethal. Here we report a posttranscriptional pathway involving the RNA-binding protein HuR as a key player in the onset of this syndrome. Under these conditions, HuR switches its function from a promoter of muscle fiber formation to become an inducer of muscle loss. HuR binds to the STAT3 ( signal transducer and activator of transcription 3) mRNA, which encodes one of the main effectors of this condition, promoting its expression both in vitro and in vivo. While HuR does not affect the stability and the cellular movement of this transcript, HuR promotes the translation of the STAT3 mRNA by preventing miR-330 ( microRNA 330)-mediated translation inhibition. To achieve this effect, HuR directly binds to a U-rich element in the STAT3 mRNA-3' untranslated region ( UTR) located within the vicinity of the miR-330 seed element. Even though the binding sites of HuR and miR-330 do not overlap, the recruitment of either one of them to the STAT3-3' UTR negatively impacts the binding and the function of the other factor. Therefore, together, our data establish the competitive interplay between HuR and miR-330 as a mechanism via which muscle fibers modulate, in part, STAT3 expression to determine their fate in response to promoters of muscle wasting.