Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Tri-institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Cell Chem Biol. 2018 Mar 15;25(3):262-267.e5. doi: 10.1016/j.chembiol.2017.12.013. Epub 2018 Jan 27.
Val-boroPro (PT-100, Talabostat) induces powerful anti-tumor immune responses in syngeneic cancer models, but its mechanism of action has not yet been established. Val-boroPro is a non-selective inhibitor of post-proline-cleaving serine proteases, and the inhibition of the highly related cytosolic serine proteases Dpp8 and Dpp9 (Dpp8/9) by Val-boroPro was recently demonstrated to trigger an immunostimulatory form of programmed cell death known as pyroptosis selectively in monocytes and macrophages. Here we show that Dpp8/9 inhibition activates the inflammasome sensor protein Nlrp1b, which in turn activates pro-caspase-1 to mediate pyroptosis. This work reveals a previously unrecognized mechanism for activating an innate immune pattern recognition receptor and suggests that Dpp8/9 serve as an intracellular checkpoint to restrain Nlrp1b and the innate immune system.
Val-boroPro（PT-100，Talabostat）在同种异体肿瘤模型中诱导强大的抗肿瘤免疫反应，但它的作用机制尚未确定。Val-boroPro 是非选择性脯氨酰肽内切酶抑制剂，最近证明其对高度相关的胞质丝氨酸蛋白酶 Dpp8 和 Dpp9（Dpp8/9）的抑制作用可选择性地在单核细胞和巨噬细胞中触发一种称为细胞焦亡的免疫刺激性程序性细胞死亡形式。在这里，我们表明 Dpp8/9 的抑制作用激活了炎症小体传感器蛋白 Nlrp1b，后者反过来又激活了前胱天蛋白酶-1 来介导细胞焦亡。这项工作揭示了一种以前未被认识到的激活先天免疫模式识别受体的机制，并表明 Dpp8/9 作为一种细胞内检查点来抑制 Nlrp1b 和先天免疫系统。
