靶向蛋白质去稳定化揭示了雌激素介导的内质网应激反应。

Raina Kanak, Noblin Devin J, Serebrenik Yevgeniy V, Adams Alison, Zhao Connie, Crews Craig M

1] Department of Chemistry, Yale University New Haven, Connecticut, USA. [2].

1] Department of Molecular, Cellular and Developmental Biology, Yale University New Haven, Connecticut, USA. [2].

Nat Chem Biol. 2014 Nov;10(11):957-62. doi: 10.1038/nchembio.1638. Epub 2014 Sep 21.

Accumulation of unfolded proteins within the endoplasmic reticulum (ER) of eukaryotic cells leads to an unfolded protein response (UPR) that either restores homeostasis or commits the cells to apoptosis. Tools traditionally used to study the UPR are proapoptotic and thus confound analysis of long-term cellular responses to ER stress. Here, we describe an ER-localized HaloTag (ERHT) protein that can be conditionally destabilized using a small-molecule hydrophobic tag (HyT36). Treatment of ERHT-expressing cells with HyT36 induces acute, resolvable ER stress that results in transient UPR activation without induction of apoptosis. Transcriptome analysis of late-stage responses to this UPR stimulus reveals a link between UPR activity and estrogen signaling.

真核细胞内质网（ER）中未折叠蛋白的积累会引发未折叠蛋白反应（UPR），该反应要么恢复内环境稳态，要么使细胞走向凋亡。传统上用于研究UPR的工具具有促凋亡作用，因此混淆了对细胞对内质网应激长期反应的分析。在此，我们描述了一种内质网定位的卤代标签（ERHT）蛋白，它可以使用小分子疏水标签（HyT36）进行条件性降解。用HyT36处理表达ERHT的细胞会诱导急性、可缓解的内质网应激，导致短暂的UPR激活而不诱导凋亡。对这种UPR刺激晚期反应的转录组分析揭示了UPR活性与雌激素信号之间的联系。