在ER-线粒体接口上的Sigma-1受体伴侣调节Ca2+) 信号和细胞存活率
1Cellular Pathobiology Unit, Plasticity and Development Section, Cellular Neurobiology Research Branch, Intramural Research Program, NIDA, NIH, DHHS, Baltimore, MD 21224, USA. thayashi@intra.nida.nih.gov
Cell
|November 6, 2007
概括
在ER-线粒体接口的sigma-1受体 (Sig-1R) 调节信号传递. 从BiP中脱离Sig-1R增强了线粒体的吸收,影响了细胞存活率和ER应激反应.
科学领域:
- 细胞生物学 细胞生物学
- 线粒体功能的功能
- 细胞内膜网膜动力学 细胞内膜网膜动力学
背景情况:
- 细胞内质网膜 (ER) 和线粒体的通信对于细胞能量生产和生存至关重要.
- 线粒体关联的ER膜 (MAM) 通过伊诺西1,4,5-三酸盐受体 (IP3Rs) 从ER直接转移 (Ca2+) 到线粒体.
研究的目的:
- 研究ER蛋白质西格玛-1受体 (Sig-1R) 作为ER-线粒体通信调节者的作用.
- 阐明Sig-1R在MAM调节信号传递的机制.
主要方法:
- 描述Sig-1R作为MAM的Ca2+敏感和配体操作的受体陪伴者.
- 在不同的ER Ca2+条件下,分析与BiP的Sig-1R复合体形成.
- 在慢性ER压力下评估Sig-1R转位.
- 评估Sig-1R水平对ER应激反应和亡的影响.
主要成果:
- 在MAM中,Sig-1R充当了Ca2+敏感和接体操作的陪伴者.
- Sig-1R通常在MAM与BiP复合;解离发生在ER Ca2+耗尽或连接体刺激时.
- 通过IP3Rs,Sig-1R解离延长了Ca2+向线粒体传递信号的时间.
- 在慢性ER压力期间,Sig-1R可以转位,其水平影响细胞命运 (抵消压力或增强细胞亡).
结论:
- 在MAM的ER陪伴机器,涉及Sig-1R,感知ER Ca2+水平.
- 这种感知机制调节了ER-线粒体Ca2+信号传递,最终导致细胞存活.
- 通过调节器官间通信,Sig-1R在压力下维持细胞平衡中起着至关重要的作用.
相关概念视频
01:29Protein Folding Quality Check in the RER
ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
01:37The Unfolded Protein Response
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...
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...
01:16Calmodulin-dependent Signaling
Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...