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

   

Authors:	Sharif, H.; Hollingsworth, L. R.; Griswold, A. R.; Hsiao, J. C.; Wang, Q.; Bachovchin, D. A.; Wu, H.
Article Title:	Dipeptidyl peptidase 9 sets a threshold for CARD8 inflammasome formation by sequestering its active C-terminal fragment
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. © 2021 Elsevier Inc.
Keywords:	cryo-em; pyroptosis; inflammasome; nlrp1; card8; dpp9; targeted degradation; val-boropro (vbp)
Journal Title:	Immunity
Volume:	54
Issue:	7
ISSN:	1074-7613
Publisher:	Cell Press
Date Published:	2021-07-13
Start Page:	1392
End Page:	1404.e10
Language:	English
DOI:	10.1016/j.immuni.2021.04.024
PUBMED:	34019797
PROVIDER:	scopus
PMCID:	PMC8423358
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85107271922&doi=10.1016%2fj.immuni.2021.04.024&partnerID=40&md5=7f97b09940ecfb88c1c4d0fc58826889
Notes:	Article -- Export Date: 2 August 2021 -- Source: Scopus

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