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-Structure paper
タイトル | Dipeptidyl peptidase 9 sets a threshold for CARD8 inflammasome formation by sequestering its active C-terminal fragment. |
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ジャーナル・号・ページ | Immunity, Vol. 54, Issue 7, Page 1392-1404.e10, Year 2021 |
掲載日 | 2021年7月13日 |
著者 | Humayun Sharif / L Robert Hollingsworth / Andrew R Griswold / Jeffrey C Hsiao / Qinghui Wang / Daniel A Bachovchin / Hao Wu / |
PubMed 要旨 | 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) ...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 NT degradation and thereby liberate the inflammasome-forming CT. Here, we report cryoelectron microscopy (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 NT degradation and by weakening ternary complex stability. |
リンク | Immunity / PubMed:34019797 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.3 - 3.86 Å |
構造データ | EMDB-22367, PDB-7jkq: EMDB-22402, PDB-7jn7: EMDB-22974: |
化合物 | ChemComp-GK2: |
由来 |
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キーワード | IMMUNE SYSTEM / HYDROLASE / CARD8 / DPP9 / inflammasome / Val-boroPro (VbP) / talabostat / innate immunity |