CASP4介导的底物裂解
中文名称
通路描述
一旦激活，caspase-4 (CASP4) 裂解气死蛋白 D (GSDMD)，GSDMD 也是 CASP1、CASP5 和 Casp11 的底物，CASP4/CASP5 是小鼠 CASP4/CASP5 的人同源物 (Shi J et al., 2015; Kayagaki N et al., 2015; Zhao Y et al., 2018; Wang K et al., 2020; Downs KP et al., 2020)。该裂解释放一个细胞毒 N 端片段 GSDMD(1-275)，其在脂质膜中形成孔道，导致炎症性细胞死亡 (pyroptosis)，以及一个 C 端片段 GSDMD(276-484)，该片段通过结合 N 端正常抑制孔道形成 (Shi J et al., 2015; Liu X et al., 2016; Ding J et al., 2016; Sborgi L et al., 2016; Aglietti RA et al., 2016; Liu Z et al., 2019; Yang J et al., 2018; Kuang S et al., 2017; Wang K et al., 2020)。此外，CASP4 (和 CASP5) 高效处理前炎介素 -18 (pro-IL-18) 的天冬氨酸残基 D36，生成其成熟、生物活性形式 (Shi X et al., 2023; Devant P et al., 2023; Exconde PM et al., 2023; 综述 Exconde PM, 2024)。结构分析表明，该裂解依赖于双价识别机制，其中前炎介素 -18 通过两个界面与 caspase-4 结合：蛋白酶外位点结合前炎介素 -18 内的疏水口袋，而 CASP4 的活性位点与位于前域四肽识别 motif 内及相邻的带电残基相互作用 (Shi X et al., 2023; Devant P et al., 2023)。相比之下，CASP4-和 CASP5 介导的前炎介素 -1β在 D27 处的裂解产生无受体刺激活性的无活性片段 (Exconde PM et al., 2023; 综述 Exconde PM, 2024)。CASP4 介导的 D116 处前炎介素 -1β的裂解，即前炎介素 -1β的激活位点，已被观察到，但效率低于前炎介素 -18 的处理 (Bibo-Verdugo B et al., 2020; Chan AH et al., 2023; Devant P et al., 2023)。CASP4 也可能参与前炎介素 -1α的处理和成熟，但尚不清楚 (Casson CN et al., 2015; Wiggins KA et al., 2019)。成熟的 IL-1 家族细胞因子通过 GSDMD 孔道释放，在哺乳动物中放大炎症反应 (Shi J et al., 2015; Kayagaki N et al., 2015; 综述 Broz P et al., 2020; Liu X et al., 2021)。
英文描述
CASP4-mediated substrate cleavage Once activated, caspase-4 (CASP4) cleaves gasdermin D (GSDMD), which is also a substrate of CASP1, CASP5, and Casp11, a murine homolog of human CASP4/CASP5 (Shi J et al., 2015; Kayagaki N et al., 2015; Zhao Y et al., 2018; Wang K et al., 2020; Downs KP et al., 2020). This cleavage releases a cytotoxic N-terminal fragment, GSDMD(1â275), which forms pores in lipid membranes, leading to pyroptosis, and a C-terminal fragment, GSDMD(276â484), which normally inhibits pore formation by binding the N-terminus (Shi J et al., 2015; Liu X et al., 2016; Ding J et al., 2016; Sborgi L et al., 2016; Aglietti RA et al., 2016; Liu Z et al., 2019; Yang J et al., 2018; Kuang S et al., 2017; Wang K et al., 2020). In addition, CASP4 (and CASP5) efficiently processes pro-interleukin-18 (pro-IL-18) at aspartic acid residue D36 to generate its mature, biologically active form (Shi X et al., 2023; Devant P et al., 2023; Exconde PM et al., 2023; reviewed by Exconde PM, 2024). Structural analyses revealed that this cleavage relies on a bivalent recognition mechanism, in which pro-IL-18 binds caspase-4 through two interfaces: the protease exosite binds a hydrophobic pocket within pro-IL-18, while the active site of CASP4 engages charged residues located within and adjacent to the tetrapeptide recognition motif in the pro-domain (Shi X et al., 2023; Devant P et al., 2023). In contrast, CASP4- and CASP5-mediated cleavage of pro-IL-1β at D27 produces an inactive fragment that lacks receptor-stimulating activity (Exconde PM et al., 2023; reviewed by Exconde PM, 2024). An alternative CASP4-mediated cleavage at D116, the canonical pro-IL-1β activation site, has been observed but occurs with lower efficiency comparing to pro-IL-18 processing (Bibo-Verdugo B et al., 2020; Chan AH et al., 2023; Devant P et al., 2023). CASP4 may also contribute to pro-IL-1α processing and maturation, though this remains less well defined (Casson CN et al., 2015; Wiggins KA et al., 2019). Mature IL-1 family cytokines are released through GSDMD pores, amplifying the inflammatory response in mammals (Shi J et al., 2015; Kayagaki N et al., 2015; reviewed by Broz P et al., 2020; Liu X et al., 2021).
所含基因
5 个基因