通过在神经退行中发生突变的E3联酶来抑制应激反应
Diane L Haakonsen1,2, Michael Heider1, Andrew J Ingersoll1
1Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA.
Nature
|January 31, 2024
概括
一种新的依赖于无处不在的机制使细胞应激反应沉默. 综合应激反应 (SIFI) 综合体的沉默因子降低了应激成分,为神经退行性疾病提供了路线图.
科学领域:
- 细胞生物学
- 应激反应的分子机制
- 神经退行性疾病研究
背景情况:
- 长时间激活应激途径可能导致细胞亡并破坏生物体的健康.
- 对于及时和局部终止应激反应的精确机制尚不清楚.
- 线粒体蛋白质进口压力是一个关键的细胞挑战.
研究的目的:
- 阐明对线粒体蛋白质进口压力的细胞反应沉默的无处不在依赖机制.
- 确定关键因素参与终止应激反应途径.
- 探索针对神经退行性疾病中应激反应终止的治疗潜力.
主要方法:
- 研究一种依赖于无处不在的压力反应沉默机制.
- 描述了综合应激反应 (SIFI) 复合体的沉默因子的作用.
- 分析了SIFI的基质识别动机和降解目标.
- 评估药物应激反应沉默对细胞存活的影响.
主要成果:
- 确定了一种依赖于全方位素的机制, 沉默细胞对线粒体蛋白质进口压力的反应.
- 综合应激反应 (SIFI) 综合体的沉默因子被发现对这一过程至关重要.
- SIFI可以降解非进口线粒体前体和应激反应成分.
- SIFI识别了双功能基质图案,这些图案决定了蛋白质的定位和稳定性,从而实现了应激解决.
- 药物抑制应激反应促进了细胞的存活,即使应激反应失败.
结论:
- 在特定的压力事件解决后,SIFI复合物提供了一个关闭一般应激反应的机制.
- 信号终止对于维持细胞存活和生物体健康至关重要.
- 针对应激反应终止提供了与线粒体进口缺陷相关的神经退行性疾病的潜在治疗策略.
相关概念视频
The Unfolded Protein Response
4.6K
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...
4.6K
Regulation of the Unfolded Protein Response
2.4K
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...
2.4K
Regulated Protein Degradation
7.3K
It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
7.3K
Neural Regulation
39.4K
Digestion begins with a cephalic phase that prepares the digestive system to receive food. When our brain processes visual or olfactory information about food, it triggers impulses in the cranial nerves innervating the salivary glands and stomach to prepare for food.
39.4K
Receptor Downregulation in MVBs
2.1K
Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
2.1K
Nonsense-mediated mRNA Decay
10.6K
The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
10.6K


