Activation of the CARD8 Inflammasome Requires a Disordered Region

• DOI: 10.1016/j.celrep.2020.108264
• Publication Date: 2020-10-13T17:57:14Z
• Authors: Ashley J. Chui; Andrew R. Griswold; Cornelius Y. Taab...; Elizabeth L. Orth; Kuo Gai; Sahana D. Rao; Daniel P. Ball; Jeffrey C. Hsiao; Daniel A. Bachovchin
• Keywords: 0303 health sciences; Inflammasomes; THP-1 Cells; Lysine; Dipeptides; Boronic Acids; Article; Neoplasm Proteins; 3. Good health; CARD Signaling Adaptor Proteins; Intrinsically Disordered Proteins; Mice; 03 medical and health sciences; HEK293 Cells; RAW 264.7 Cells; Proteolysis; Proteostasis; Animals; Humans; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases

Several cytosolic pattern-recognition receptors (PRRs) form multiprotein complexes called canonical inflammasomes in response to intracellular danger signals. Canonical recruit and activate caspase-1 (CASP1), which turn cleaves activates inflammatory cytokines gasdermin D (GSDMD), inducing pyroptotic cell death. Inhibitors of the dipeptidyl peptidases DPP8 DPP9 (DPP8/9) both human NLRP1 CARD8 inflammasomes. have different N-terminal regions but similar C-terminal that undergo autoproteolysis generate two non-covalently associated fragments. Here, we show DPP8/9 inhibition a proteasomal degradation pathway targets disordered misfolded proteins for destruction. CARD8's N terminus contains region ∼160 amino acids is recognized destroyed by this pathway, thereby freeing its fragment CASP1 induce pyroptosis. Thus, serves as an alarm signal activation proteins.