卡斯帕斯3表现出酵母甲卡斯帕斯蛋白质稳定功能,该功能保护线粒体免受有毒的TDP43聚合物的影响
Steve Brunette1, Anupam Sharma1,2, Ryan Bell1
1Regenerative Medicine Program, Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON K1H 8L6, Canada.
Microbial cell (Graz, Austria)
|August 7, 2023
概括
卡斯巴酶3通常与细胞死亡有关,实际上可能通过清除像TDP-43这样的有毒蛋白质团块来保护细胞. 这种蛋白酶作为一种重要的蛋白质稳定因子,对神经退行性疾病中的细胞健康至关重要.
科学领域:
- 生物化学 生物化学
- 细胞生物学 细胞生物学
- 神经科学是一个神经科学.
背景情况:
- 酶3激活是已知的细胞死亡标志物,其活性升高与像ALS这样的神经退行性疾病有关.
- 肌缩侧面硬化症 (ALS) 涉及TDP-43蛋白聚合物,这些聚合物被怀疑在病理上激活caspase 3.
- 新出现的证据表明,酶3在细胞生存,生长,分化和应激适应方面发挥作用.
研究的目的:
- 通过分散有毒的蛋白质聚合物来研究酶3是否作为蛋白质稳定因子.
- 为了确定人体酶3能否替代酵母甲酶 (ScMCA1) 在管理蛋白质聚合方面.
- 在TDP-43聚合的背景下,探索酶3在细胞健康和器官功能中的作用.
主要方法:
- 酵母替代模型使用人体酶3替代酵母甲酶 (ScMCA1).
- 在酵母和哺乳动物细胞中分析TDP-43聚合和蛋白相互作用.
- 蛋白质组学分析,以在caspase 3中断时识别蛋白质关联.
- 在被抑制的caspase3细胞中评估线粒体功能.
主要成果:
- 人类酶3成功地限制了酵母中的TDP-43聚合,功能性地取代了Scmca1.
- 在酵母中破坏酶3导致TDP-43与线粒体蛋白之间的有害关联.
- 在小鼠和人类骨肌细胞中抑制caspase 3导致TDP-43的累积和线粒体功能受损.
结论:
- 卡斯帕酶3可能作为蛋白质稳定因子起作用,而不仅仅是细胞死亡媒介.
- 这种蛋白酶有助于分散有毒的TDP-43内含物,从而保护有机细胞功能.
- 酶3在与蛋白质聚合和细胞应激相关的疾病中起着保护作用.
相关概念视频
Caspases
12.6K
Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside...
12.6K
Translocation of Proteins into the Mitochondria
3.2K
Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
3.2K
The Intrinsic Apoptotic Pathway
6.6K
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
6.6K
Mitochondrial Precursor Proteins
2.6K
Mitochondrial precursors are partially unfolded or loosely folded polypeptide chains. Newly synthesized precursors are inhibited from spontaneously folding into their native conformation by the cytosolic chaperones, heat shock proteins 70 (Hsp70), and mitochondrial import stimulation factors (MSFs). Precursors bound to MSFs are guided to the TOM70-TOM37 receptors, while precursors bound to Hsp70 chaperones are targetted to TOM20-TOM22 receptor complexes.
Most of the mitochondrial...
Most of the mitochondrial...
2.6K
The Proteasome
892
Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
892
Export of Misfolded Proteins out of the ER
3.7K
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...
3.7K


