Activation of the CARD8 Inflammasome Requires a Disordered Region.
| Publication Type | Academic Article |
| Authors | Chui A, Griswold A, Taabazuing C, Orth E, Gai K, Rao S, Ball D, Hsiao J, Bachovchin D |
| Journal | Cell Rep |
| Volume | 33 |
| Issue | 2 |
| Pagination | 108264 |
| Date Published | 10/13/2020 |
| ISSN | 2211-1247 |
| Keywords | CARD Signaling Adaptor Proteins, Inflammasomes, Intrinsically Disordered Proteins, Neoplasm Proteins |
| Abstract | Several cytosolic pattern-recognition receptors (PRRs) form multiprotein complexes called canonical inflammasomes in response to intracellular danger signals. Canonical inflammasomes recruit and activate caspase-1 (CASP1), which in turn cleaves and activates inflammatory cytokines and gasdermin D (GSDMD), inducing pyroptotic cell death. Inhibitors of the dipeptidyl peptidases DPP8 and DPP9 (DPP8/9) activate both the human NLRP1 and CARD8 inflammasomes. NLRP1 and CARD8 have different N-terminal regions but have similar C-terminal regions that undergo autoproteolysis to generate two non-covalently associated fragments. Here, we show that DPP8/9 inhibition activates a proteasomal degradation pathway that targets disordered and misfolded proteins for destruction. CARD8's N terminus contains a disordered region of ∼160 amino acids that is recognized and destroyed by this degradation pathway, thereby freeing its C-terminal fragment to activate CASP1 and induce pyroptosis. Thus, CARD8 serves as an alarm to signal the activation of a degradation pathway for disordered and misfolded proteins. |
| DOI | 10.1016/j.celrep.2020.108264 |
| PubMed ID | 33053349 |
| PubMed Central ID | PMC7594595 |