细胞内膜网膜应激通过改变跨膜受体的处理来破坏信号传输
Michaela Bosakova1,2,3, Sara P Abraham1,2,3, Davis Wachtell4
1Department of Biology, Faculty of Medicine, Masaryk University, 62500, Brno, Czech Republic.
Cell communication and signaling : CCS
|April 30, 2025
概括
细胞内膜网膜 (ER) 的压力通过减少细胞表面的成熟的跨膜受体,损害了细胞的通信. 通过陪伴者恢复ER功能,重新建立受体信号,提供治疗见解.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 病理学 病理学 病理学
背景情况:
- 细胞通信依赖于通过内质网膜 (ER) - 戈尔吉系统处理的跨膜受体.
- 与癌症和神经退行等疾病相关的ER压力涉及蛋白质错误折叠和过度生产.
- 对于ER应激对跨膜受体功能和细胞信号传递的影响尚不清楚.
研究的目的:
- 研究ER压力如何影响细胞表面的局部化和跨膜受体的信号传递.
- 确定特定的受体和参与ER压力诱导的通信缺陷的细胞机制.
- 评估ER减压策略在恢复受体功能方面的潜力.
主要方法:
- 使用的疾病模型包括多发性骨髓瘤,慢性淋巴细胞白血病和骨质变异不完美.
- 在ER压力条件下分析了关键跨膜受体 (FGFR3,ROR1,FGFR1,LRP6,FZD5,PTH1R) 的细胞表面表达.
- 评估了下游的信号通路,并使用化学伴奏剂 (tauroursodeoxycholic acid) 和蛋白伴奏剂 (BiP) 来减轻ER压力.
主要成果:
- 在疾病模型中,ER压力导致了细胞表面成熟的跨膜受体的显著损失.
- 这种损失是由于受体产生减少和细胞内不成熟的受体形式的保留增加造成的.
- 用化学或蛋白质陪伴剂治疗恢复了受体成熟和下游信号,减轻了ER压力效应.
结论:
- ER压力通过损害跨膜受体处理和细胞表面定位来破坏细胞通信.
- 恢复ER平衡可以挽救受体功能和信号,突出了ER压力的新病理作用.
- 这些发现对于理解ER压力相关疾病和开发受体向疗法至关重要.
相关概念视频
01:17Role of ER in the Secretory Pathway
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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...
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01:37The Unfolded Protein Response
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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...
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01:31Regulation of the Unfolded Protein Response
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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...
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01:27Post-translational Translocation of Proteins to the RER
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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...
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01:32Export of Misfolded Proteins out of the ER
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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...
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01:39Endoplasmic Reticulum
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The Endoplasmic Reticulum (ER) in eukaryotic cells is a substantial network of interconnected membranes with diverse functions, from calcium storage to biomolecule synthesis. A primary component of the endomembrane system, the ER manufactures phospholipids critical for membrane function throughout the cell. Additionally, the two distinct regions of the ER specialize in the manufacture of specific lipids and proteins.
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