The unfolded protein response and endoplasmic reticulum protein targeting machineries converge on the stress sensor IRE1
The unfolded protein response and endoplasmic reticulum protein targeting machineries converge on the stress sensor IRE1
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DOI：
10.7554/elife.43036
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发表时间：
2018-12-24
期刊：
影响因子：
7.7
通讯作者：
Walter, Peter
中科院分区：
文献类型：
--
作者：
Acosta-Alvear, Diego;Karagoez, G. Elif;Walter, Peter
内质网（ER）的蛋白质折叠能力受到信号通路网络（称为未折叠蛋白质反应（UPR））的严格调节。UPR传感器监测ER折叠状态，根据需要调整ER折叠能力。为了了解UPR传感器IRE1如何维持ER稳态，我们在体内以单核苷酸精确度鉴定了RNA与IRE1的零长度交联。我们发现，IRE1特异性交联ER靶向的mRNA，SRP RNA，核糖体和转移RNA的子集。交联位点聚集在核糖体表面的离散区域中，从A位点跨越到多肽出口通道。此外，IRE1以高亲和力结合纯化的80S核糖体，表明与ER结合的核糖体相关。我们的研究结果表明，ER蛋白的移位和靶向机制与UPR一起调节ER的蛋白折叠负荷。
The protein folding capacity of the endoplasmic reticulum (ER) is tightly regulated by a network of signaling pathways, known as the unfolded protein response (UPR). UPR sensors monitor the ER folding status to adjust ER folding capacity according to need. To understand how the UPR sensor IRE1 maintains ER homeostasis, we identified zero-length crosslinks of RNA to IRE1 with single nucleotide precision in vivo. We found that IRE1 specifically crosslinks to a subset of ER-targeted mRNAs, SRP RNA, ribosomal and transfer RNAs. Crosslink sites cluster in a discrete region of the ribosome surface spanning from the A-site to the polypeptide exit tunnel. Moreover, IRE1 binds to purified 80S ribosomes with high affinity, indicating association with ER-bound ribosomes. Our results suggest that the ER protein translocation and targeting machineries work together with the UPR to tune the ER's protein folding load.