RIPK1 介导的程序性坏死
中文名称
通路描述
RIPK1 介导的程序性坏死是指由受体相互作用丝氨酸/苏氨酸激酶蛋白 1（RIPK1）和 RIPK3 依赖性坏死引起的细胞死亡，也称为程序性坏死。RIPK1 和 RIPK3 的激酶活性对于人类细胞系和遗传小鼠模型中的坏死性细胞死亡至关重要。坏死性坏死的启动可由激活外源性凋亡信号通路的相同死亡配体刺激，如肿瘤坏死因子（TNF）α、Fas 配体（FasL）和 TRAIL（TNF 相关凋亡诱导配体）或 Toll 样受体 3 和 4 配体。与凋亡不同，坏死性坏死在 caspase 被抑制时最优诱导。最近已发现抑制非 caspase 依赖性坏死的小分子抑制剂坏死素（necrostatins），它们已被证明能抑制 RIPK1 的激酶活性。当 caspase 8 活性受损时，凋亡形态的细胞死亡可转变为坏死表型，否则活性 caspase 8 通过蛋白酶切割 RIPK1 和 RIPK3 来阻断坏死性坏死。在特定病理生理条件下或通过药物抑制 caspase 活性时，去泛素化的 RIPK1 与配体激酶 RIPK3 发生物理和功能相互作用，形成坏死素，即由 RIPK1 和 RIPK3 组成的坏死性坏死诱导复合物。在坏死素中，RIPK1 和 RIPK3 通过其 RIP 同源相互作用基序（RHIM）基序相互结合。RHIM 基序可促进 RIPK1:RIPK3 寡聚化，使其形成类淀粉样纤维结构。RIPK3 随后与混合 lineage 激酶结构域样蛋白（MLKL）相互作用。MLKL 的 RIPK3 激活机制尚不完全清楚，可能因物种而异。小鼠 MLKL 的激活依赖于 RIPK3 的短暂结合以促进伪激酶结构域的磷酸化，而人类 MLKL 的稳定招募由坏死素中的 RIPK3 是激活人类 MLKL 的另一个关键步骤。RIPK3 介导的磷酸化被认为启动 MLKL 寡聚化、膜转位和膜破坏。研究表明，在坏死性坏死诱导后，MLKL 在人类细胞中向细胞膜和膜内细胞器（如线粒体、溶酶体、内体和高尔基体）移位，但通过依赖高尔基体 - 微管 - 肌动蛋白的机制促进膜转位，膜破坏导致死亡。MLKL 下游的坏死性坏死调节和执行机制尚不清楚。MLKL 介导的细胞膜破坏的精确寡聚形式一直存在争议。然而，显微镜数据显示，MLKL 在人类细胞内的细胞质坏死素中组装成更高分子量的物种，并在 RIPK3 磷酸化后转运至细胞膜。在细胞膜上，磷酸化 MLKL 形成异质的高级组装体，被认为导致细胞通透性增加，释放 DAMPs 以引发炎症反应。MLKL 还具有非坏死性功能，如调节内体转运或 MLKL 诱导的 NLRP3 炎症小体激活。虽然 RIPK1、RIPK3 和 MLKL 是坏死性坏死通路的核心信号组分，但许多额外的分子已被提出以正负调节该通路。目前，这一图像正在快速发展，随着新调节剂的不断发现而演变。
英文描述
Defective OGG1 Substrate Processing The majority of OGG1 mutants have been tested for their ability to excise 8-oxoguanine (8oxoG) from damaged DNA, while a small number of mutants have been tested for the ability to remove FapyG from DNA.
The following OGG1 mutants show at least a partial loss of their ability to remove 8oxoG:
OGG1 R46Q (Audebert, Chevillard et al. 2000; Audebert, Radicella et al. 2000);
OGG1 R154H (Audebert, Radicella et al. 2000, Bruner et al. 2000);
OGG1 R131Q (Chevillard et al. 1998, Bruner et al. 2000, Anderson and Dagget 2009);
OGG1 R229Q (Hyun et al. 2000, Hyun et al. 2002, Hill and Evans 2007);
OGG1 P266fs139* (Mao et al. 2007).
OGG1 R46L and OGG1 R131G have not been functionally studied but have been reported in cancer and predicted to be pathogenic. They are annotated as candidate disease variants based on their similarity with OGG1 R46Q and OGG1 R131Q, respectively.
OGG1 S326C, a frequent variant in European and Asian populations, is susceptible to oxidation, which diminishes catalytic activity under conditions of oxidative stress (Dherin et al. 1999, Yamane et al. 2004, Kershaw and Hodges 2012, Moritz et al. 2014).
The following OGG1 mutants show at least a partial loss of their ability to remove FapyG:
OGG1 R46Q (Audebert, Radicella et al. 2000);
OGG1 R154H (Audebert, Radicella et al. 2000).
OGG1 R46L has not been functionally studied but has been reported in cancer and predicted to be pathogenic. It is annotated as a candidate disease variant for FapyG excision, based on its similarity with OGG1 R46Q.
The following OGG1 mutants show at least a partial loss of their ability to remove 8oxoG:
OGG1 R46Q (Audebert, Chevillard et al. 2000; Audebert, Radicella et al. 2000);
OGG1 R154H (Audebert, Radicella et al. 2000, Bruner et al. 2000);
OGG1 R131Q (Chevillard et al. 1998, Bruner et al. 2000, Anderson and Dagget 2009);
OGG1 R229Q (Hyun et al. 2000, Hyun et al. 2002, Hill and Evans 2007);
OGG1 P266fs139* (Mao et al. 2007).
OGG1 R46L and OGG1 R131G have not been functionally studied but have been reported in cancer and predicted to be pathogenic. They are annotated as candidate disease variants based on their similarity with OGG1 R46Q and OGG1 R131Q, respectively.
OGG1 S326C, a frequent variant in European and Asian populations, is susceptible to oxidation, which diminishes catalytic activity under conditions of oxidative stress (Dherin et al. 1999, Yamane et al. 2004, Kershaw and Hodges 2012, Moritz et al. 2014).
The following OGG1 mutants show at least a partial loss of their ability to remove FapyG:
OGG1 R46Q (Audebert, Radicella et al. 2000);
OGG1 R154H (Audebert, Radicella et al. 2000).
OGG1 R46L has not been functionally studied but has been reported in cancer and predicted to be pathogenic. It is annotated as a candidate disease variant for FapyG excision, based on its similarity with OGG1 R46Q.
所含基因
1 个基因