传递 RNA 的向是内质网膜应激信号站点
Tomás Aragón1, Eelco van Anken, David Pincus
1Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94158-2517, USA. Tomas.Aragon@ucsf.edu
Nature
|December 17, 2008
概括
细胞内膜网膜 (ER) 的压力触发了展开的蛋白质反应 (UPR). Ire1的激活会导致与ER结合的mRNA聚合,从而实现UPR信号传递和蛋白质折叠调节.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- 细胞内膜网膜 (ER) 的压力源于蛋白质错误折叠,激活了未折叠蛋白质反应 (UPR).
- 通过像Ire1这样的传感器来调节UPR,该传感器将HAC1mRNA (酵母) 或XBP1 (转生动物) 拼接起来,以恢复ER平衡.
- 通过其内子和5' UTR对HAC1mRNA的翻译控制调节了Hac1合成.
研究的目的:
- 在UPR期间调查Ire1激活和HAC1mRNA拼接的分子机制.
- 阐明Ire1聚类和mRNA招募如何为UPR信号提供贡献.
- 为了确定保存元素在HAC1mRNA向中的作用.
主要方法:
- 酵母遗传学和分子生物学技术.
- 使用显微镜分析Ire1的寡合化和局部化.
- mRNA-蛋白相互作用研究和功能测试.
主要成果:
- Ire1的激活导致其聚合到离散的ER膜焦点中,形成更高阶的寡合体.
- 未分离的HAC1mRNA通过其3' UTR中的双部分元素被招募到这些Ire1焦点.
- Ire1集群或mRNA招募的中断显著损害了UPR信号传输.
- HAC1 3' UTR 元素可以将其他被抑制的mRNA向Ire1焦点.
结论:
- 对Ire1信号中心的mRNA招募是一种控制真核生物基因表达的新机制.
- 这一过程对于高效的UPR激活和细胞适应ER压力至关重要.
- 这些发现揭示了ER膜基因表达调节的新范式.
相关概念视频
02:22Regulated mRNA Transport
5.7K
In eukaryotes, transcription and translation are compartmentalized; an mRNA is first synthesized in the nucleus and then selectively transported to the cytoplasm for protein synthesis. Before transport, a pre-mRNA undergoes several steps of post-transcriptional modifications including splicing, 5' capping, and the addition of a poly-adenine tail. Various proteins bind to the pre-mRNA during these modifications. The mRNA transport takes place with the help of multiple proteins playing...
5.7K
01:17Role of ER in the Secretory Pathway
6.3K
Eukaryotic cells have a special pathway that enables communication between various intracellular membrane-bound compartments and also with the extracellular environment. This pathway is termed as the secretory pathway.
Components of the secretory pathway
About a third of proteins synthesized in the cell are sorted via the secretory route. They shuffle between different compartments in membrane-bound vesicles until they reach their final destination. The main intracellular compartments involved...
Components of the secretory pathway
About a third of proteins synthesized in the cell are sorted via the secretory route. They shuffle between different compartments in membrane-bound vesicles until they reach their final destination. The main intracellular compartments involved...
6.3K
01:34Directing Proteins to the Rough Endoplasmic Reticulum
12.0K
The organelle-specific signaling sequences direct proteins synthesized in the cytosol to their final destination like ER, mitochondria, peroxisomes, etc. Some of the proteins directed to ER are then trafficked via vesicles to other organelles within the cell or the extracellular environment through the Golgi complex. For example, the rough ER synthesizes soluble proteins for transportation to the lysosomes or secretion out of the cell. It can also synthesize transmembrane proteins that can...
12.0K
01:37The Unfolded Protein Response
5.6K
The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
5.6K
01:32Export of Misfolded Proteins out of the ER
4.3K
After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
4.3K
01:31Regulation of the Unfolded Protein Response
2.2K
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.2K