IRE1通过处理XBP-1mRNA将内质网膜负载与分泌能力相结合
Marcella Calfon1, Huiqing Zeng, Fumihiko Urano
1Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.
Nature
|January 10, 2002
概括
在较高的真核生物中,未折叠的蛋白质反应 (UPR) 是通过 XBP-1 mRNA 的 IRE1-依赖拼接来调节的. 这一过程对于细胞适应子质内网膜应激的过程至关重要.
科学领域:
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
- 遗传学 是一个遗传学.
背景情况:
- 展开的蛋白质反应 (UPR) 通过调节蛋白质折叠能力来维持内 плазма网膜 (ER) 稳态.
- 在酵母中,通过IRE1介导的HAC1mRNA的处理来激活UPR,从而导致Hac1转录因子的合成.
- 在元动物中IRE1信号通路的理解较少,特别是关于它们在UPR激活中的作用.
研究的目的:
- 调查IRE1和XBP-1在元动物中UPR中的作用.
- 阐明由IRE1.1激活XBP-1mRNA的机制.
- 了解ER负载调节在较高的真核生物中的生理意义.
主要方法:
- 在Caenorhabditis elegans (ire-1和xbp-1突变) 中进行基因淘汰研究.
- 在C. elegans和小鼠中对UPR激活的反应中对XBP-1mRNA剪接的分析.
- 在试验室中使用净化小鼠IRE1和XBP-1mRNA进行了切割试验.
主要成果:
- 在ire-1或xbp-1中的突变取消了C. elegans中的UPR.
- 在C. elegans和小鼠中UPR激活诱导了XBP-1mRNA的IRE1依赖拼接.
- 在UPR期间,XBP-1蛋白积累仅从拼接的mRNA中观察到.
- 鼠标IRE1在体外直接切割XBP-1mRNA,将其确定为直接目标.
结论:
- 由 IRE1 进行的 XBP-1 mRNA 拼接是 UPR 激活元动物的保存机制.
- 这条通路对于特殊的分泌细胞功能至关重要,比如免疫球蛋白分泌.
- 通过这种调节机制,生理ER负载会通过这种调节机制影响更高的真核生物的发育决策.
相关概念视频
01:17Role of ER in the Secretory Pathway
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...
01:45ER Retrieval Pathway
In the secretory pathway, vesicles transport proteins from one cellular compartment to another in forward transport to deliver the protein to its correct location. Occasionally, misfolded proteins and incorrect proteins escape their original compartments, and a retrieval pathway is used to return the escaped proteins to their original compartment.
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
01:34Directing Proteins to the Rough Endoplasmic Reticulum
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...
01:27Post-translational Translocation of Proteins to the RER
A sizable fraction of proteins destined for ER are first synthesized in the cell cytosol and then transported across the ER membrane–a process called post-translational translocation. Similar to cotranslationally translocated proteins, these proteins also use the Sec translocon complex to enter the ER lumen.
Targeting proteins to the ER
Hsp40 and Hsp70 chaperone molecules bind the translated proteins in the cytosol to prevent their folding. The chaperone binding helps to keep the signal...
Targeting proteins to the ER
Hsp40 and Hsp70 chaperone molecules bind the translated proteins in the cytosol to prevent their folding. The chaperone binding helps to keep the signal...
01:32Export of Misfolded Proteins out of the ER
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...
01:31Regulation of the Unfolded Protein Response
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...