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Inhibition of Dpp8/9 Activates the Nlrp1b Inflammasome
Cell Chemical Biology ( IF 8.6 ) Pub Date : 2018-01-30 , DOI: 10.1016/j.chembiol.2017.12.013
Marian C. Okondo , Sahana D. Rao , Cornelius Y. Taabazuing , Ashley J. Chui , Sarah E. Poplawski , Darren C. Johnson , Daniel A. Bachovchin

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.

中文翻译:

抑制Dpp8 / 9激活Nlrp1b炎性小体

Val-boroPro(PT-100,Talabostat)在同基因癌症模型中诱导强大的抗肿瘤免疫反应,但其作用机理尚未建立。Val-boroPro是脯氨酸裂解后的丝氨酸蛋白酶的非选择性抑制剂,最近已证明Val-boroPro对高度相关的胞浆丝氨酸蛋白酶Dpp8和Dpp9(Dpp8 / 9)的抑制可触发程序性免疫刺激形式。在单核细胞和巨噬细胞中选择性地发生细胞死亡,称为焦磷酸化。在这里,我们显示Dpp8 / 9抑制激活炎性体传感器蛋白Nlrp1b,进而激活pro-caspase-1介导焦磷酸化。
更新日期:2018-03-16
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