Dipeptidyl peptidase 9 sets a threshold for CARD8 inflammasome formation by sequestering its active C-terminal fragment.
| Publication Type | Academic Article |
| Authors | Sharif H, Hollingsworth L, Griswold A, Hsiao J, Wang Q, Bachovchin D, Wu H |
| Journal | Immunity |
| Volume | 54 |
| Issue | 7 |
| Pagination | 1392-1404.e10 |
| Date Published | 05/20/2021 |
| ISSN | 1097-4180 |
| Keywords | CARD Signaling Adaptor Proteins, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Inflammasomes, Neoplasm Proteins |
| Abstract | 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. |
| DOI | 10.1016/j.immuni.2021.04.024 |
| PubMed ID | 34019797 |
| PubMed Central ID | PMC8423358 |