Reflux of Endoplasmic Reticulum proteins to the cytosol inactivates tumor suppressors.
Reflux of Endoplasmic Reticulum proteins to the cytosol inactivates tumor suppressors.
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DOI：
10.15252/embr.202051412
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发表时间：
2021-05-05
期刊：
影响因子：
7.7
通讯作者：
Igbaria A
中科院分区：
文献类型：
--
作者：
Sicari D;Centonze FG;Pineau R;Le Reste PJ;Negroni L;Chat S;Mohtar MA;Thomas D;Gillet R;Hupp T;Chevet E;Igbaria A
在过去的几十年中，许多研究报道了内质网（ER）驻留蛋白在胞质溶胶中的存在。然而，这些蛋白质重新定位的机制以及它们是否发挥胞质功能仍然未知。我们发现，一个子集的ER管腔蛋白积累在胶质母细胞瘤细胞从小鼠和人类肿瘤分离的胞质溶胶。在培养的细胞中，ER蛋白质回流到胞质溶胶发生后，ER蛋白质稳态扰动。使用ER管腔蛋白前梯度2（AGR 2）作为概念证明，我们测试了回流蛋白是否在胞质溶胶中获得新的功能。我们发现，回流，胞质AGR 2结合和抑制肿瘤抑制p53。这些数据表明，ER反流构成了一种ER监视机制，在应激时从其内容物中释放ER，通过获得胞质功能为肿瘤细胞提供选择性优势-我们将这种现象称为ER至胞质信号传导（ERCYS）。癌细胞中的内质网（ER）应激导致一部分ER蛋白逃逸到胞质溶胶中，在胞质溶胶中它们结合并抑制关键信号通路以增加癌细胞适应性。
In the past decades, many studies reported the presence of endoplasmic reticulum (ER)‐resident proteins in the cytosol. However, the mechanisms by which these proteins relocate and whether they exert cytosolic functions remain unknown. We find that a subset of ER luminal proteins accumulates in the cytosol of glioblastoma cells isolated from mouse and human tumors. In cultured cells, ER protein reflux to the cytosol occurs upon ER proteostasis perturbation. Using the ER luminal protein anterior gradient 2 (AGR2) as a proof of concept, we tested whether the refluxed proteins gain new functions in the cytosol. We find that refluxed, cytosolic AGR2 binds and inhibits the tumor suppressor p53. These data suggest that ER reflux constitutes an ER surveillance mechanism to relieve the ER from its contents upon stress, providing a selective advantage to tumor cells through gain‐of‐cytosolic functions—a phenomenon we name ER to Cytosol Signaling (ERCYS). Endoplasmic Reticulum (ER) stress in cancer cells causes a subset of ER proteins to escape to the cytosol where they bind and inhibit key signaling pathways to increase cancer cell fitness.