揭示ESCRT依赖性自细胞关闭的生理影响,通过准VPS37A全素E2变异类型域VPS37A
Kouta Hamamoto1, Xinwen Liang1, Ayako Ito2
1Division of Pediatric Hematology and Oncology, Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
Cell reports
|November 28, 2024
概括
由于VPS37A突变引起的小鼠自细胞关闭受损,导致蛋白质积聚和神经元问题. 然而,这些小鼠可以存活下来,这表明它们对蛋白质聚合起着保护作用.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
背景情况:
- 宏自 (自) 是一种细胞过程,涉及自细胞的形成和成熟.
- 抑制自细胞关闭的后果尚不清楚.
研究的目的:
- 研究受损自细胞关闭对细胞功能和生物体健康的影响.
- 分析ESCRT-I复合体VPS37A子单元在自细胞生物发生中的作用.
主要方法:
- 在VPS37A基因中产生和分析具有特定突变 (Δ43-139) 的小鼠,以准其无素E2变异类型 (UEVL) β链.
- 在突变小鼠中评估自流,蛋白质聚合,神经元功能和组织异常.
- 临近LC3蛋白质组学,以识别受突变影响的相互作用蛋白质和通路.
主要成果:
- VPS37A UEVL突变损害了大量自流,导致p62/SQSTM1和无处不在的蛋白质的积累.
- 同卵性突变小鼠表现出神经元功能障碍,生长迟缓和组织异常,但大约一半的小鼠活到成年.
- 这种突变导致活性TANK结合激酶1 (TBK1) 在光体上积聚,促进p62酸化和包容形成.
结论:
- 缺陷的自细胞关闭会破坏细胞蛋白质稳定,并导致各种生理缺陷.
- LC3结合的光体在蛋白质聚合和分离中发挥作用,可能减轻蛋白质毒性.
- 针对VPS37A提供了对自的复杂机制及其对疾病的影响的见解.
相关概念视频
Intralumenal Vesicles and Multivesicular Bodies
3.4K
Intraluminal vesicles (ILVs) are small vesicles 50-80 nm in diameter formed during the maturation of early endosomes. A specialized endosome containing numerous ILVs is called a multivesicular body (MVB). ILVs contain internalized molecules such as antigens, nucleic acids, proteins, and metabolites. Some of these molecules are released from the MVBs inside exosomes and are transported to other cells. Other MVBs contain molecules that are retained in the ILVs and are later degraded within the...
3.4K
Delivery Pathways to the Lysosome
6.2K
Eukaryotic cells use different mechanisms to eliminate toxic waste obsolete and worn-out substances. Lysosomes play a pivotal role in this, and hence, these substances are carried to the lysosome from other parts of the cell and extracellular space through different pathways. The most elaborately studied pathways to the lysosome are the endocytic pathways.
Endocytosis
In endocytosis, the cell membrane takes up macromolecules and particles from the surrounding medium. Clathrin-mediated...
Endocytosis
In endocytosis, the cell membrane takes up macromolecules and particles from the surrounding medium. Clathrin-mediated...
6.2K
ER Retrieval Pathway
3.8K
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...
3.8K
The Unfolded Protein Response
4.4K
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...
4.4K
Regulated Protein Degradation
7.1K
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...
7.1K
Export of Misfolded Proteins out of the ER
3.5K
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...
3.5K


