Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore.
Department of Infection, Immunity and Cardiovascular Diseases, The University of Sheffield, Sheffield, United Kingdom.
Front Immunol. 2019 Jul 5;10:1556. doi: 10.3389/fimmu.2019.01556. eCollection 2019.
The inflammasome is an intracellular multi-protein complex that orchestrates the release of the pro-inflammatory cytokines IL-1β and IL-18, and a form of cell death known as pyroptosis. Tyrosine phosphorylation of the inflammasome sensors NLRP3, AIM2, NLRC4, and the adaptor protein, apoptosis-associated speck-like protein (ASC) has previously been demonstrated to be essential in the regulation of the inflammasome. By using the pharmacological protein tyrosine phosphatase (PTPase) inhibitor, phenylarsine oxide (PAO), we have demonstrated that tyrosine dephosphorylation is an essential step for the activation of the NLRP3 and AIM2 inflammasomes in human and murine macrophages. We have also shown that PTPase activity is required for ASC nucleation leading to caspase-1 activation, IL-1β, and IL-18 processing and release, and cell death. Furthermore, by site-directed mutagenesis of ASC tyrosine residues, we have identified the phosphorylation of tyrosine Y60 and Y137 of ASC as critical for inflammasome assembly and function. Therefore, we report that ASC tyrosine dephosphorylation and phosphorylation are crucial events for inflammasome activation.
炎症小体是一种细胞内多蛋白复合物，可协调促炎细胞因子 IL-1β 和 IL-18 的释放，以及一种称为细胞焦亡的细胞死亡形式。先前已经证明，炎症小体传感器 NLRP3、AIM2、NLRC4 和衔接蛋白凋亡相关斑点样蛋白 (ASC) 的酪氨酸磷酸化对于炎症小体的调节至关重要。通过使用药理学蛋白酪氨酸磷酸酶 (PTPase) 抑制剂苯砷氧化物 (PAO)，我们已经证明，在人类和鼠巨噬细胞中，酪氨酸去磷酸化是 NLRP3 和 AIM2 炎症小体激活的必要步骤。我们还表明，PTPase 活性对于 ASC 成核导致 caspase-1 激活、IL-1β 和 IL-18 加工和释放以及细胞死亡是必需的。此外，通过 ASC 酪氨酸残基的定点突变，我们已经确定 ASC 酪氨酸 Y60 和 Y137 的磷酸化对于炎症小体组装和功能至关重要。因此，我们报告 ASC 酪氨酸去磷酸化和磷酸化是炎症小体激活的关键事件。
