The acyltransferase Gpc1 is both a target and an effector of the unfolded protein response in Saccharomyces cerevisiae.
The acyltransferase Gpc1 is both a target and an effector of the unfolded protein response in Saccharomyces cerevisiae.
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DOI：
10.1016/j.jbc.2023.104884
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发表时间：
2023-07
影响因子：
4.8
通讯作者：
Patton-Vogt, Jana
中科院分区：
文献类型：
--
作者：
Hrach, Victoria Lee;King, William R.;Nelson, Laura D.;Conklin, Shane;Pollock, John A.;Patton-Vogt, Jana
未折叠蛋白反应 (UPR) 对蛋白毒性和膜双层应激敏感，这两者均由 ER 蛋白 Ire1 感知。当 Ire1 被激活时，它会剪接 HAC1 mRNA，产生一种转录因子，该转录因子针对参与蛋白质稳态和脂质代谢等的基因。主要膜脂磷脂酰胆碱 (PC) 受到磷脂酶介导的脱酰作用，产生甘油磷酸胆碱 (GPC)，然后通过 PC 脱酰/再酰化途径 (PC-DRP) 对 GPC 进行再酰化。再酰化事件通过两步过程发生，首先由 GPC 酰基转移酶 Gpc1 催化，然后由 Ale1 酰化 lyso-PC 分子。然而，Gpc1 是否对 ER 双层稳态至关重要尚不清楚。使用改进的 C14-胆碱-GPC 放射性标记方法，我们首先证明 Gpc1 的丢失会导致 PC-DRP 合成 PC 的废除，并且 Gpc1 与 ER 共定位。然后我们探讨了 Gpc1 作为 UPR 的靶点和效应器的作用。暴露于 UPR 诱导化合物衣霉素、DTT 和刀豆氨酸会导致 GPC1 信息的 Hac1 依赖性增加。此外，缺乏 Gpc1 的细胞对这些蛋白毒性应激源表现出更高的敏感性。肌醇限制已知会通过双层应激诱导 UPR，也会诱导 GPC1 表达。最后，我们证明 GPC1 的丢失会诱导 UPR。 gpc1Δ 突变体在表达 Ire1 突变体的菌株中表现出 UPR 上调，该突变体对未折叠蛋白无反应，表明双层应激是观察到的上调的原因。总的来说，我们的数据表明 Gpc1 在酵母 ER 双层稳态中发挥着重要作用。
The unfolded protein response (UPR) is sensitive to proteotoxic and membrane bilayer stress, both of which are sensed by the ER protein Ire1. When activated, Ire1 splices HAC1 mRNA, producing a transcription factor that targets genes involved in proteostasis and lipid metabolism, among others. The major membrane lipid phosphatidylcholine (PC) is subject to phospholipase-mediated deacylation, producing glycerophosphocholine (GPC), followed by reacylation of GPC through the PC deacylation/reacylation pathway (PC-DRP). The reacylation events occur via a two-step process catalyzed first by the GPC acyltransferase Gpc1, followed by acylation of the lyso-PC molecule by Ale1. However, whether Gpc1 is critical for ER bilayer homeostasis is unclear. Using an improved method for C14-choline-GPC radiolabeling, we first show that loss of Gpc1 results in abrogation of PC synthesis through PC-DRP and that Gpc1 colocalizes with the ER. We then probe the role of Gpc1 as both a target and an effector of the UPR. Exposure to the UPR-inducing compounds tunicamycin, DTT, and canavanine results in a Hac1-dependent increase in GPC1 message. Further, cells lacking Gpc1 exhibit increased sensitivity to those proteotoxic stressors. Inositol limitation, known to induce the UPR via bilayer stress, also induces GPC1 expression. Finally, we show that loss of GPC1 induces the UPR. A gpc1Δ mutant displays upregulation of the UPR in strains expressing a mutant form of Ire1 that is unresponsive to unfolded proteins, indicating that bilayer stress is responsible for the observed upregulation. Collectively, our data indicate an important role for Gpc1 in yeast ER bilayer homeostasis.
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DOI：
10.1016/j.bbalip.2013.03.002
发表时间：
2013-06-01
影响因子：
4.8
作者：
De Smet, Cedric H.;Cox, Ruud;de Kroon, Anton I. P. M.
通讯作者：
de Kroon, Anton I. P. M.
影响因子：
4.8
作者：
Bishop, Andrew C.;Ganguly, Shantanu;Patton-Vogt, Jana
通讯作者：
Patton-Vogt, Jana
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：
3.2
作者：
Hanscho, Michael;Ruckerbauer, David E.;Natter, Klaus
通讯作者：
Natter, Klaus
影响因子：
7.7
作者：
Di Santo, Rachael;Aboulhouda, Soufiane;Weinberg, David E.
通讯作者：
Weinberg, David E.