Dipeptidyl peptidase 9 sets a threshold for CARD8 inflammasome formation by sequestering its active C-terminal fragment.
Dipeptidyl peptidase 9 sets a threshold for CARD8 inflammasome formation by sequestering its active C-terminal fragment.
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DOI：
10.1016/j.immuni.2021.04.024
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发表时间：
2021-07-13
期刊：
影响因子：
32.4
通讯作者：
Wu H
中科院分区：
文献类型：
--
作者：
Sharif H;Hollingsworth LR;Griswold AR;Hsiao JC;Wang Q;Bachovchin DA;Wu H
CARD 8检测细胞内危险信号并形成半胱天冬酶-1激活炎性小体。与相关的炎性体传感器NLRP 1一样，CARD 8自动加工成非共价结合的N-末端（NT）和C-末端（CT）片段，并结合细胞二肽基肽酶DPP 8和9（DPP 8/9）。某些炎症相关信号，包括DPP 8/9抑制剂Val-boroPro（VbP）和HIV蛋白酶，诱导蛋白酶体介导的N-末端降解，从而释放炎性小体形成CT。在这里，我们报告cryo-EM结构的CARD 8绑定到DPP 9，揭示了一个阻遏三元复合物组成的DPP 9，全长CARD 8，和CARD 8-CT。与NLRP 1-CT不同，CARD 8-CT不与DPP 8/9活性位点相互作用，也不直接被VbP取代。然而，较大的DPP 8/9活性位点探针可以直接削弱这种复合物在体外，和VBP本身似乎破坏这种复合物，也许间接地，在细胞中。因此，DPP 8/9抑制剂可以通过促进CARD 8 N-末端降解和通过削弱三元复合物稳定性来激活CARD 8炎性体。炎性小体是多蛋白复合物，其响应于胞质危险信号而执行焦亡。DPP 9通过未知的机制调节CARD 8炎性体。在此，Sharif等人报道了与DPP 9结合的CARD 8的冷冻-EM结构，并显示该复合物抑制蛋白酶体下游的CARD 8炎性体活化。
CARD8 detects intracellular danger signals and forms a caspase-1 activating inflammasome. Like the related inflammasome sensor NLRP1, CARD8 autoprocesses into noncovalently associated N-terminal (NT) and C-terminal (CT) fragments, and binds the cellular dipeptidyl peptidases DPP8 and 9 (DPP8/9). Certain danger-associated signals, including the DPP8/9 inhibitor Val-boroPro (VbP) and HIV protease, induce proteasome-mediated N-terminal degradation, and thereby liberate the inflammasome-forming CT. Here we report cryo-EM structures of CARD8 bound to DPP9, revealing a repressive ternary complex consisting of DPP9, full-length CARD8, and CARD8-CT. Unlike NLRP1-CT, CARD8-CT does not 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 promoting CARD8 N-terminal degradation, and by weakening ternary complex stability. Inflammasomes are multiprotein complexes that execute pyroptosis in response to cytosolic danger signals. DPP9 regulates the CARD8 inflammasome by unknown mechanisms. Here, Sharif et al. report cryo-EM structures of CARD8 bound to DPP9 and show that this complex inhibits CARD8 inflammasome activation downstream of the proteasome.
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通讯作者：
Wu H