Messenger RNA targeting to endoplasmic reticulum stress signalling sites.
Messenger RNA targeting to endoplasmic reticulum stress signalling sites.
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DOI：
10.1038/nature07641
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发表时间：
2009-02-05
期刊：
影响因子：
64.8
通讯作者：
Walter, Peter
中科院分区：
文献类型：
--
作者：
Aragon, Tomas;van Anken, Eelco;Pincus, David;Serafimova, Iana M.;Korennykh, Alexei V.;Rubio, Claudia A.;Walter, Peter
真核细胞内质网蛋白质折叠能力的缺陷导致内质网应激并触发未折叠蛋白质反应。ER应激由Ire 1（一种跨膜激酶/核糖核酸内切酶）感知，Ire 1启动编码关键转录激活因子（酵母中的Hac 1或后生动物中的XBP-1）的mRNA的非常规剪接。在没有ER应激的情况下，核糖体停滞在未剪接的HAC 1 mRNA上。翻译控制是由HAC 1内含子和HAC 1 5′非翻译区（5′UTR）之间的碱基配对相互作用施加的。内含子切除后，tRNA连接酶连接切断的外显子，解除翻译阻断，并允许从剪接的HAC 1 mRNA合成Hac 1。Hac 1反过来驱动包含7-8%酵母基因组的UPR基因表达程序，以抵消ER应激。我们发现，在激活后，Ire 1分子在ER膜中聚集成离散的高阶寡聚体，未剪接的HAC 1 mRNA通过3′非翻译区（3′UTR）中包含的保守的二分靶向元件被募集到这些寡聚体中。Ire 1聚集或HAC 1 mRNA募集的破坏损害UPR信号传导。HAC 1 3′UTR元件足以将其他mRNA靶向Ire 1焦点，只要它们的翻译受到抑制。内含子提供的翻译抑制满足了对HAC 1 mRNA的这一要求。mRNA向信号中心的募集为真核基因表达的调控提供了新的范例。
Deficiencies in the protein folding capacity of the endoplasmic reticulum (ER) in all eucaryotic cells lead to ER stress and triggers the unfolded protein response (UPR). ER stress is sensed by Ire1, a transmembrane kinase/endoribonuclease, which initiates the non-conventional splicing of the mRNA encoding a key transcription activator, Hac1 in yeast or XBP-1 in metazoans. In the absence of ER stress, ribosomes are stalled on unspliced HAC1 mRNA. The translational control is imposed by a base pairing interaction between the HAC1 intron and the HAC1 5′ untranslated region (5′UTR). After excision of the intron, tRNA ligase joins the severed exons, lifting the translational block and allowing synthesis of Hac1 from the spliced HAC1 mRNA to ensue. Hac1 in turn drives the UPR gene expression program comprising 7–8% of the yeast genome to counteract ER stress. We show here that upon activation, Ire1 molecules cluster in the ER membrane into discrete foci of higher-order oligomers, to which unspliced HAC1 mRNA is recruited by means of a conserved bipartite targeting element contained in the 3′ untranslated region (3′UTR). Disruption of either Ire1 clustering or of HAC1 mRNA recruitment impairs UPR signaling. The HAC1 3′UTR element is sufficient to target other mRNAs to Ire1 foci, as long as their translation is repressed. Translational repression afforded by the intron fulfills this requirement for HAC1 mRNA. Recruitment of mRNA to signaling centers provides a new paradigm for the control of eukaryotic gene expression.
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