XBP1s Links the Unfolded Protein Response to the Molecular Architecture of Mature N-Glycans.
XBP1s Links the Unfolded Protein Response to the Molecular Architecture of Mature N-Glycans.
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DOI：
10.1016/j.chembiol.2015.09.006
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发表时间：
2015-10-22
影响因子：
--
通讯作者：
Shoulders MD
中科院分区：
文献类型：
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作者：
Dewal MB;DiChiara AS;Antonopoulos A;Taylor RJ;Harmon CJ;Haslam SM;Dell A;Shoulders MD
成熟n -糖的分子结构是动态的，对正常和病理过程都有影响。因此，阐明调节n链糖的细胞机制是至关重要的。未折叠蛋白反应（UPR）通常通过定义伴侣蛋白和质量控制蛋白的水平来维持分泌途径中的蛋白质稳态。在这里，我们采用化学生物学方法来研究UPR调控，结果表明，UPR的XBP1s转录因子的应激非依赖性激活也诱导了一组n-聚糖成熟相关的酶。下游的结果是由xbp1s激活的细胞产生的n -糖蛋白上的特定杂交和复杂n -聚糖的明显转变，我们用质谱法对其进行了表征。脉冲追踪研究将这种转变特别归因于n -聚糖加工的改变，而不是降解或分泌速率的变化。我们的发现暗示XBP1s在n -糖蛋白生物合成中起着新的作用，揭示了细胞内应激反应与细胞外n -糖蛋白分子结构之间的重要联系。
The molecular architecture of the mature N-glycome is dynamic, with consequences for both normal and pathologic processes. Elucidating cellular mechanisms that modulate the N-linked glycome is, therefore, crucial. The unfolded protein response (UPR) is classically responsible for maintaining proteostasis in the secretory pathway by defining levels of chaperones and quality control proteins. Here, we employ chemical biology methods for UPR regulation to show that stress-independent activation of the UPR’s XBP1s transcription factor also induces a panel of N-glycan maturation-related enzymes. The downstream consequence is a distinctive shift towards specific hybrid and complex N-glycans on N-glycoproteins produced from XBP1s-activated cells, which we characterize by mass spectrometry. Pulse-chase studies attribute this shift specifically to altered N-glycan processing, rather than to changes in degradation or secretion rates. Our findings implicate XBP1s in a new role for N-glycoprotein biosynthesis, unveiling an important link between intracellular stress responses and the molecular architecture of extracellular N-glycoproteins.