IRE1 RNase控制了CD95介导的细胞死亡
Diana Pelizzari-Raymundo1,2, Victoria Maltret1,2, Manon Nivet1,2
1Inserm U1242, University of Rennes, Rennes, France.
EMBO reports
|February 22, 2024
概括
展开的蛋白质反应传感器IRE1调节了CD95/Fas死亡受体表达和癌症中的功能. 抑制IRE1增强了CD95介导的细胞死亡在质母细胞瘤和三阴性乳腺癌.
科学领域:
- 癌症生物学 癌症生物学
- 分子细胞生物学 分子细胞生物学
- 信号通道的信号通道
背景情况:
- 展开蛋白质响应 (UPR) 和死亡受体 (DR) 信号往往被选择为瘤进展.
- IRE1是UPR的关键传感器,与癌细胞存活和增殖有关.
研究的目的:
- 研究IRE1在控制死亡受体CD95/Fas表达和功能的调控作用.
- 探索针对质母细胞瘤和三阴性乳腺癌的IRE1-CD95轴的治疗潜力.
主要方法:
- IRE1活动的遗传和药理抑制.
- 分析CD95mRNA表达及其通过受调IRE1-依赖RNA衰变 (RIDD) 的调节.
- 在癌细胞系和体内小鼠模型中评估CD95L诱导的细胞死亡.
主要成果:
- IRE1抑制增加了CD95表达,并使质母细胞瘤和三阴性乳腺癌细胞对CD95L诱导的死亡敏感.
- CD95 mRNA 是 IRE1 介导的 RIDD 的目标.
- 在小鼠中,IRE1抑制降低了CD95介导的肝毒性.
- 过度表达XBP1s增加了CD95表达和细胞死亡敏感性.
结论:
- IRE1通过RIDD和XBP1s对CD95依赖细胞死亡进行双重控制.
- 这项研究揭示了IRE1和CD95在癌症中发出信号之间的新型调节联系.
- 向IRE1可能提供一种治疗策略,以增强CD95介导的抗瘤免疫力.
相关概念视频
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
The Extrinsic Apoptotic Pathway
6.4K
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...
6.4K
Caspases
12.5K
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...
12.5K
Experimental RNAi
6.1K
RNA interference (RNAi) is a cellular mechanism that inhibits gene expression by suppressing its transcription or activating the RNA degradation process. The mechanism was discovered by Andrew Fire and Craig Mello in 1998 in plants. Today, it is observed in almost all eukaryotes, including protozoa, flies, nematodes, insects, parasites, and mammals. This precise cellular mechanism of gene silencing has been developed into a technique that provides an efficient way to identify and determine the...
6.1K
The 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
Necrosis
4.5K
Necrosis is considered as an “accidental” or unexpected form of cell death that ends in cell lysis. The first noticeable mention of “necrosis” was in 1859 when Rudolf Virchow used this term to describe advanced tissue breakdown in his compilation titled “Cell Pathology”.
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...
4.5K


