A critical role of DDRGK1 in endoplasmic reticulum homoeostasis via regulation of IRE1α stability.
A critical role of DDRGK1 in endoplasmic reticulum homoeostasis via regulation of IRE1α stability.
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DDRGK1 通过调节 IRE1a 稳定性在内质网稳态中发挥关键作用
DOI：
10.1038/ncomms14186
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发表时间：
2017-01-27
影响因子：
16.6
通讯作者：
Cong YS
中科院分区：
文献类型：
--
作者：
Liu J;Wang Y;Song L;Zeng L;Yi W;Liu T;Chen H;Wang M;Ju Z;Cong YS
内质网（ER）稳态的紊乱诱导ER应激并导致未折叠蛋白反应（UPR）的激活，这是一种适应性反应，当稳态未恢复时，促进细胞存活或触发细胞凋亡。DDRGK 1是一种ER膜蛋白，是泛素折叠修饰因子1（Ufm 1）系统的关键组分。然而，DDRGK 1在ER稳态中的功能和机制在很大程度上是未知的。在这里，我们发现DDRGK 1的耗竭诱导ER应激，并增强ER应激诱导的癌细胞和造血干细胞（HSC）凋亡。DDRGK 1的缺失抑制IRE 1 α-XBP 1信号传导，并通过靶向ER应激传感器IRE 1 α激活PERK-eIF 2 α-CHOP凋亡途径。我们进一步证明DDRGK 1通过与IRE 1 α的激酶结构域的相互作用来调节IRE 1 α蛋白的稳定性，这依赖于其磺酰化修饰。总之，我们的研究结果提供了证据，DDRGK 1是必不可少的ER稳态调节。DDRGK 1是一种受到Ufm 1修饰的ER膜蛋白，但其在ER稳态中的功能尚不清楚。在这里，作者表明，ufmylated DDRGK 1与ER应激传感器蛋白IRE 1a相互作用并稳定，进而抑制ER应激和细胞凋亡。
Disturbance of endoplasmic reticulum (ER) homoeostasis induces ER stress and leads to activation of the unfolded protein response (UPR), which is an adaptive reaction that promotes cell survival or triggers apoptosis, when homoeostasis is not restored. DDRGK1 is an ER membrane protein and a critical component of the ubiquitin-fold modifier 1 (Ufm1) system. However, the functions and mechanisms of DDRGK1 in ER homoeostasis are largely unknown. Here, we show that depletion of DDRGK1 induces ER stress and enhances ER stress-induced apoptosis in both cancer cells and hematopoietic stem cells (HSCs). Depletion of DDRGK1 represses IRE1α-XBP1 signalling and activates the PERK-eIF2α-CHOP apoptotic pathway by targeting the ER-stress sensor IRE1α. We further demonstrate that DDRGK1 regulates IRE1α protein stability via its interaction with the kinase domain of IRE1α, which is dependent on its ufmylation modification. Altogether, our results provide evidence that DDRGK1 is essential for ER homoeostasis regulation. DDRGK1 is an ER membrane protein that is subject to Ufm1 modification, but its function in ER homeostasis is unknown. Here, the authors show that ufmylated DDRGK1 interacts with and stabilizes the ER-stress sensor protein IRE1a, in turn repressing ER stress and apoptosis.