Iron affects Ire1 clustering propensity and the amplitude of endoplasmic reticulum stress signaling.
Iron affects Ire1 clustering propensity and the amplitude of endoplasmic reticulum stress signaling.
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DOI：
10.1242/jcs.201715
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发表时间：
2017-10-01
影响因子：
4
通讯作者：
Schuldiner M
中科院分区：
文献类型：
--
作者：
Cohen N;Breker M;Bakunts A;Pesek K;Chas A;Argemí J;Orsi A;Gal L;Chuartzman S;Wigelman Y;Jonas F;Walter P;Ernst R;Aragón T;van Anken E;Schuldiner M
未折叠蛋白反应（UPR）允许细胞根据需要调整分泌途径的容量。Ire1是内质网（ER）应激传感器和UPR中枢激活因子，从酿酒酵母（Saccharomyces cerevisiae）到人类都保守。在内质网应激条件下，Ire1聚集成可实现最佳UPR激活的焦点。为了发现影响Ire1聚类的因素，我们使用表达Ire1 - mcherry的全基因组酵母突变文库进行了高含量筛选。我们对UPR诱导后的菌株进行了成像，发现154株菌株的Ire1聚类发生了变化。hit中富含铁和血红素效应物以及结合蛋白。通过药理消耗和补充，我们证实了铁（Fe3+）影响酵母和人类细胞中的UPR激活。我们认为Ire1聚类倾向取决于膜组成，这是由血红素依赖的甾醇生物合成控制的。我们的研究结果强调了进入UPR的多种细胞功能，并强调了协调维持体内平衡所需的细胞器之间的相互作用。为了对内质网中的折叠应力做出反应，细胞激活了保守的传感器Ire1。我们发现铁是最佳Ire1激活所必需的，这是因为麦角甾醇的生物合成需要铁。
The unfolded protein response (UPR) allows cells to adjust secretory pathway capacity according to need. Ire1, the endoplasmic reticulum (ER) stress sensor and central activator of the UPR is conserved from the budding yeast Saccharomyces cerevisiae to humans. Under ER stress conditions, Ire1 clusters into foci that enable optimal UPR activation. To discover factors that affect Ire1 clustering, we performed a high-content screen using a whole-genome yeast mutant library expressing Ire1–mCherry. We imaged the strains following UPR induction and found 154 strains that displayed alterations in Ire1 clustering. The hits were enriched for iron and heme effectors and binding proteins. By performing pharmacological depletion and repletion, we confirmed that iron (Fe3+) affects UPR activation in both yeast and human cells. We suggest that Ire1 clustering propensity depends on membrane composition, which is governed by heme-dependent biosynthesis of sterols. Our findings highlight the diverse cellular functions that feed into the UPR and emphasize the cross-talk between organelles required to concertedly maintain homeostasis. To respond to folding stress in the ER, cells activate the conserved sensor Ire1. We show that iron is required for optimal Ire1 activation and suggest this is because iron is required for ergosterol biosynthesis.
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影响因子：
3.3
作者：
Lajoie P;Moir RD;Willis IM;Snapp EL
通讯作者：
Snapp EL
影响因子：
4.3
作者：
Eden E;Lipson D;Yogev S;Yakhini Z
通讯作者：
Yakhini Z
影响因子：
7.8
作者：
Kimata, Yukio;Ishiwata-Kimata, Yuki;Ito, Tatsuhiko;Hirata, Aiko;Suzuki, Tomohide;Oikawa, Daisuke;Takeuchi, Masato;Kohno, Kenji
通讯作者：
Kohno, Kenji
DOI：
10.1007/978-1-61779-276-2_8
发表时间：
2011-01-01
期刊：
NETWORK BIOLOGY: METHODS AND APPLICATIONS
影响因子：
--
作者：
Cohen, Yifat;Schuldiner, Maya
通讯作者：
Schuldiner, Maya
影响因子：
5.4
作者：
Dull, T;Zufferey, R;Naldini, L
通讯作者：
Naldini, L