美国哈佛大学吴皓、纪念斯隆凯特琳癌症中心Daniel A. Bachovchin等研究人员合作发现，二肽基肽酶9通过隔离其活性C端片段来调节CARD8炎性小体形成的阈值。2021年5月20日，《免疫》杂志在线发表了这项成果。

研究人员表示，CARD8检测细胞内的危险信号并形成caspase-1激活的炎性小体。像相关的炎症小体传感器NLRP1一样，CARD8自动加工成非共价结合的N端（NT）和C端（CT）片段，并结合细胞二肽基肽酶DPP8和9（DPP8/9）。某些与危险相关的信号，包括DPP8/9抑制因子Val-boroPro（VbP）和HIV蛋白酶，可诱导蛋白酶体介导的NT降解，从而释放形成炎症小体的CT。

研究人员报道了与DPP9结合的CARD8的冷冻电镜（cryo-EM）结构，从而揭示出由DPP9、全长CARD8和CARD8-CT组成的阻抑性三元复合物。与NLRP1-CT不同，CARD8-CT不与DPP8/9活性位点相互作用，也不被VbP直接取代。但是，较大的DPP8/9活性位点探针可以在体外直接削弱该复合物，而VbP本身似乎可以在细胞中间接破坏该复合物。因此，DPP8/9抑制因子可通过促进CARD8 NT降解并减弱三元复合物的稳定性来激活CARD8炎性体。 

附：英文原文

Title: Dipeptidyl peptidase 9 sets a threshold for CARD8 inflammasome formation by sequestering its active C-terminal fragment

Author: Humayun Sharif, L. Robert Hollingsworth, Andrew R. Griswold, Jeffrey C. Hsiao, Qinghui Wang, Daniel A. Bachovchin, Hao Wu

Issue&Volume: 2021-05-20

Abstract: CARD8 detects intracellular danger signals and forms a caspase-1 activating inflammasome.Like the related inflammasome sensor NLRP1, CARD8 autoprocesses into noncovalentlyassociated N-terminal (NT) and C-terminal (CT) fragments and binds the cellular dipeptidylpeptidases DPP8 and 9 (DPP8/9). Certain danger-associated signals, including the DPP8/9inhibitor Val-boroPro (VbP) and HIV protease, induce proteasome-mediated NT degradationand thereby liberate the inflammasome-forming CT. Here, we report cryoelectron microscopy(cryo-EM) structures of CARD8 bound to DPP9, revealing a repressive ternary complexconsisting of DPP9, full-length CARD8, and CARD8-CT. Unlike NLRP1-CT, CARD8-CT doesnot interact with the DPP8/9 active site and is not directly displaced by VbP. However,larger DPP8/9 active-site probes can directly weaken this complex in vitro, and VbP itself nevertheless appears to disrupt this complex, perhaps indirectly,in cells. Thus, DPP8/9 inhibitors can activate the CARD8 inflammasome by promotingCARD8 NT degradation and by weakening ternary complex stability.

DOI: 10.1016/j.immuni.2021.04.024

Source: https://www.cell.com/immunity/fulltext/S1074-7613(21)00186-2