CARD8 N端的疏水性调整了炎酶体激活的情况
Lydia P Tsamouri1, Jeffrey C Hsiao1, Qinghui Wang2
1Pharmacology Program of the Weill Cornell Graduate School of Medical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Cell chemical biology
|July 11, 2024
概括
抗氧化剂对CARD8炎症酶的疏水性修饰直接激活它. 这些修改破坏了CARD8的N端区域的稳定性,促进了炎症酶激活,并指示了囊蛋白.
科学领域:
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- 蛋白质毒性压力是已知的CARD8炎症酶的激活剂.
- 控制CARD8炎症酶激活的精确机制和信号尚不完全理解.
- 以前发现,疏水激素捕获抗氧化剂 (RTA) 通过未知的途径增强了CARD8炎症酶激活的作用.
研究的目的:
- 阐明水性RTAs增强CARD8炎症酶激活的机制.
- 为了确定RTA介导的CARD8激活所涉及的特定分子标和修改.
- 研究氨酸残留物在CARD8调节和对蛋白质毒性压力的反应中的作用.
主要方法:
- 化学修饰试验检测RTAs对CARD8的化.
- 西方涂抹和蛋白质酶抑制试验用于评估CARD8蛋白质的稳定性和降解.
- 炎症酶激活试验 (例如,IL-1β释放) 作为对RTA,电友和CARD8突变的反应.
- 局部定向的突变发生,以以异黄素取代CARD8的氨酸残留物.
主要成果:
- 疏水性RTAs,如JSH-23,在CARD8.8的N端无序区域中直接基化氨酸残留物.
- 这种化破坏了CARD8的抑制性N端片段的稳定,导致其蛋白质体降解.
- 降解使CARD8的C端片段从自身抑制中释放出来,从而激活炎症酶.
- 与之无关的疏水电友和CARD8囊蛋白转变为异氨酸的突变模仿了RTA诱导的炎症酶激活的强化.
结论:
- CARD8的N终端囊蛋白是调节炎性酶激活的疏水性修饰的关键标.
- 水性修饰和随后的CARD8 N端的降解代表了与蛋白质折叠应激相关的CARD8炎症酶激活的新机制.
- 这些发现突出了CARD8 N-终端半氨酸在感知和响应蛋白质毒性压力的作用,为炎症细胞调节提供了新的见解.
相关概念视频
01:17The Extrinsic Apoptotic Pathway
6.3K
The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
6.3K
01:17Phagocytosis of Apoptotic Cells
3.7K
Cells undergoing apoptosis form apoptotic bodies that must be removed immediately to prevent inflammation, autoimmune diseases, and necrosis. Phagocytosis is carried out by professional phagocytes such as macrophages or immature dendritic cells. Non-professional phagocytes such as epithelial cells and fibroblasts also take part in this process; however, they are not as effective as professional phagocytes.
Normal cells contain receptors that prevent them from being recognized...
Normal cells contain receptors that prevent them from being recognized...
3.7K
01:24Caspases
12.4K
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...
12.4K
01:19Translocation of Proteins into the Mitochondria
3.1K
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,...
3.1K
01:31The Intrinsic Apoptotic Pathway
6.5K
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...
6.5K
01:15Activation of Integrins
3.4K
Integrins bind ligands and transmit information from outside the cell to inside or vice-versa through an "outside-in signaling" or "inside-out signaling."
In "outside-in signaling," external factors in the extracellular space bind to exposed ligand binding sites on integrins. This causes the inactive protein to undergo a conformational change to become active. Integrins are often clustered on the cell membrane. Repetitive and regularly spaced ligand binding...
In "outside-in signaling," external factors in the extracellular space bind to exposed ligand binding sites on integrins. This causes the inactive protein to undergo a conformational change to become active. Integrins are often clustered on the cell membrane. Repetitive and regularly spaced ligand binding...
3.4K